Lynn Margulis has sent the opening statement for her blog tour below. You should feel free to respond to it, raise other questions of any relevant sort, or say whatever you want in the comments; she’ll be along later today to respond to those that interest her. I will be policing the comments, so trolls, please don’t bother; serious comments only, and keep in mind that she’s only going to respond to a limited subset, so make ’em good.
In addition, she’ll be available later today in the Pharyngula chat room (channel #pharyngula on irc.zirc.org; if you don’t have an IRC client, that link will let you use your browser to join in) from 12:00-1:30pm ET. Dive in there for a more interactive give-and-take with Dr Margulis.
What a pleasure to write openly for Pharyngula even though, in principle, I am leery, even with this blog, of any internet participation. The haste and style online by its very breezy nature generates misinterpretation and misunderstanding. Nothing online written about me is entirely accurate, except perhaps my address at the University of Massachusetts.
Although misunderstanding permeates all human communication, the internet amplifies these tendencies. Sound bite-hype is far more useful to those who assert religious truths and would banish authentic science from the public sphere than to the scholar or scientist. Science itself, and even more so, science writing, ever cautious, ever tentative and ever questioning is permeated with boring hesitancies and stuttering qualifications. Most readers simply ignore it since they find it incomprehensible. The more accurate the scientific description, the more daunting the language to any outsider. The more clear the expression of a scientific idea is, the more specialized the terminology. The clearest scientific ideas are mathematical equations opaque to all but the specialist.
So, when reporters and popular writers attempt to communicate real science the plagues of distortion, misunderstanding and misrepresentation are inevitable. Any statement outside the immediate purview of the detailed science tends to be “translated” into common language. To express new ideas that challenge the paradigm in which the scientist works new language is required. If the language is too new neither the scientist nor the science popularizer is understood. Especially when one’s work is heterodox to the prevailing trend -it is easy to be dismissed as a “crank” or “on the fringe.” Or, even more likely, to be ignored. The convenient fiction, created by marketers and politicians, that “consensus” plays a major role in original science, helps to generate confusion in the lay public about the vast difference between established scientific fact and ideologically-driven nonsense.
Scientists seek evidence. Eclipses could not be predicted, calendars could not be distributed, tide tables could not be published, airplanes could not be built to fly, food plants not grown, bridges nor buildings built, in the absence of precise knowledge of celestial mechanics, gravity, air flow, soil nutrients, flowering plant sexuality, metal compression and tensional strengths, etc. Scientific facts, scientists know, lie in the details. Explanatory power, falsifiable prediction, reproducible experimental results underlie all scientific theory. Within the detailed framework there are no “scientific controversies”. Theories explain, hypotheses make precise predictions either verifiable or not, results are either reproducible or they aren’t. The most serious communication problem is that specialized knowledge, an arcane literature and years of specialized training are required for participation in any science and all science by its very nature is severely limited to its objects of study. No botanist can participate meaningfully in nuclear physics nor can physicists analyse genetic data. Science communicators, even the very best, and there many (e,g, those who write for Science News, Nature, Science and the New York Times Tuesday pages, National Public Radio and the like) can not comprehensibly describe anything without bias and oversimplification, ever. No writing, if it is to be widely understood, can be without bias. I believe that no meaningful distinction or description of anything, science included, can be made without an historical, including natural-historical, context. Yet most scientists live in the “now”; they tend to lack a long view and any knowledge outside the limits of their own specialized field. Sometimes their “field” is more a budget constraint or a whim of a dead scholar than a natural science. Some “fields”, clearly are not natural science, like the field called “cancer”. This implies that science writing too unavoidably displays bias, prejudice, nationalism, profound ignorance, incompleteness and other manifestations of “slanted truths”.
Scientists too often know little about the cultural and historical context of their ideas. Neo-Darwinians biologists, for example, really believe that “evolution” is a subfield of biology, especially zoology. Hence they ignore the non-zoological components of evolutionary science (e.g., all of historical geology including especially paleontology; environmental science, ecology, atmospheric chemistry, microbiology, etc.) They rarely acknowledge that their theoretical frames derive from an Anglophone-capitalist model, and inevitably carry the prejudices, assumptions and philosophical orientations of our milieu. Because most people interested in evolution live in an Anglophone-capitalist culture, assumptions of neo-Darwinians are unstated. Concepts such as the validity of “cost-benefit” and “competition vs. co-operation” terminology or the superiority of mathematical analysis are uncritically assumed. Many unstated assumptions are made because of the bias of the “evolutionary biologists”, the majority of whom have animal biology/zoological training who share our cultural orientation. There is, in fact, paltry evidence for the neo-Darwinian “thought-style”. The staunch neo-Darwinist claims have become less and less valid as information from other fields (e.g., molecular biology and the fossil record) has increased. It is not unusual, especially in the science of evolution, that theories contradictory to the neo-Darwinian “thought-style” are ignored or rejected, not on the basis of their claims, or proof of those claims, but on the, often unconscious, grounds that they do not agree with our biases. Read Ludwik Fleck.
So here we have an opportunity for open discussion – to listen to nature, to perceive the nature of nature, to reveal scientifically-documented facts beyond prejudices. We attempt, with civil dialogue based on sound science, to achieve, in good faith, an understanding of each other and the world. Science is limited, what is known for sure is miniscule in contrast to the great unknown, but the deliberate faith-based distortion of what really is known is despicable. We will avoid the cant, rant and desperate attempt to distort so common on both sides in the so-called “religion-vs science” debate. Whiteheadian philosophers, many Unitarian and Buddhist scholars, all true scientists agree with David Bohm’s sentiment that “science is the search for truth” whether or not we like that truth. And Emily Dickinson’s sentiment, from her poem “Tell all the Truth but tell it Slant ” is even more compelling:
As Lightning to the Children eased
With explanation kind
The Truth must dazzle gradually
Or every man be blind–Lynn Margulis,
Mar 10, 2007
I would appreciate it if Prof. Margulis would clarify her position on the relationship, if any, of HIV and AIDS. There appears to be some confusion on her position relative to this issue due to a review of a book by Prof Duesberg who is a noted HIV/AIDS denier.
Prof. Margulis,
What significance do you attatch to epigenetic processes in evolution?
“I would appreciate it if Prof. Margulis would clarify her position on the relationship, if any, of HIV and AIDS.”
Ditto!!
I would appreciate a clarification about specific “staunch Neo-Darwinist claims” that are referenced in this sentence from her statement.
I would also appreciate an elaboration on what she means by Neo-Darwinisn. Is this the idea that natural selection + random mutation is the driving force behind evolution?
Also does she have specific examples of theories that have been rejected because they do not match the Neo-Darwinian “thought-style?”
I’d quite like to know what “staunch neo-Darwinist claims” have been falsified by molecular biology, given that nearly every recent work I’ve read about evolution relies quite heavily on it.
Robert: At the risk of getting too snarky too soon, presumably her endosymbiont theory falls into that category.
Dr. Margulis, you said:
“The staunch neo-Darwinist claims have become less and less valid as information from other fields (e.g., molecular biology and the fossil record) has increased.”
Could you provide an example of each case,i.e., where information from molecular biology, and also the fossil record, has lessened the validity of neo-Darwinist claims?
Even a link would suffice, if this seems too tedious.
Also (just curious) do you have any thought on the relationship between long-term memory and instinct (if this is within your purview)?
Except that her endosymbiont theory is now widely accepted. Perhaps it did face opposition simply because it deviated from the accepted theories of the time. But eventually it won out because of the evidence. Considering her choice in quoting Dickinson in saying that truth must be revealed gradually or everyone would be made blind it would seem that that can’t just be the only thing she means.
Plus it doesn’t make the most convincing argument to say that “Neo-Darwinists” are rejecting theories out of hand, and the only example you have is one that is now widely accepted.
It just seems like her post is very similiar to claims we often hear from the Discovery Institute (confusingly so). I suppose that may be unfair, but I think with a post like that we all deserve to hear some evidence and examples backing some of her claims up.
Quotemine alert!
I give this 5 days to appear in ID literature!
In truth, I find the whole entry disappointing. Its defensive nature puts me off. Talk to us about biology and evolution, Dr. Margulis!
For example, explain your battle to get your heterodox ideas of the symbiotic origin of organelles published, and how they ultimately became orthodoxy. Tell us about your latest ideas (origin of eukaryotes): why you believe them and the evidence that makes you do so.
Also, I’d be interested in your opinion of an idea proposed by Fritjof Capra in “The Web of Life”, that organisms are not objects (like rocks), but self-perpetuating patterns (sort of like the whirlpool that forms when you drain the bathtub).
This is a strong claim, but also very broad and perhaps unfalsifiable. What concepts would you propose to replace these “Anglophone-capitalist” ones? – and how would that improve the practice of science?
Right, I’m sure no socialist government would ever need to conduct cost-benefit analyses… [bangs head on desk]
Prof. Margulis’ publisher, Chelsea Green, has the transcript of an interview she gave to Astrobiology Magazine. It lays out some of her critique of neo-Darwinism and a lot of the basics of endosymbiosis.
http://www.chelseagreen.com/2007/items/luminousfish/Interview
http://www.chelseagreen.com/2007/items/luminousfish/Interview
“Neo-Darwinism comes from the combination of two ideas. The acceptance that Darwin is right about all organisms on Earth having common ancestry and that evolution of life has occurred. But that Gregor Mendel is also right when he shows that inheritance factors are simply recombined, they don’t change through time.
For example, you cross a red flower and a white flower – a rose, say – and you get a pink rose; and then you cross the pink rose back to the parents, you get ratios of red, pink and white that are absolutely identical to the parents. You don’t lose the red or lose the white – ever. That’s what Mendel showed. In other words, the genetic factors are simply recombined; there’s no evolution.
Now Mendel is often touted to be this backwater monk who played with his garden peas. But Mendel was in touch with the pope. He knew damn well what was going on with the concept of evolution and did not like it.
The supporters of neo-Darwinism, which is also called the modern synthesis, wanted to reconcile – they had to reconcile – Darwinian change through time with this brilliant, experimentally proven concept of Gregor Mendel.
This field they invented is called evolutionary biology by a lot of people, or sometimes population genetics. I think the whole thing’s corrupt. I think it’s repulsively corrupt. Because it has no reference in the real world. It was made from the beginning as a very clever generalization to combine the fact of Darwinian change through time, which seems to be based on fossils and lots of other evidence, with the evident fact that Mendel was right about genetic factors recombining. And so it developed a superstructure, a theory of which only a very small part could be verified by science. And it was called population genetics, because the word evolution, at least in this country, is a dirty word amongst a lot of people.”
I would love to see what PZ has to say in regards to this quote. Hell I would like some clarification as to what is corrupt and has no reference in the real world in regards to evolution.
You know, I did read a little Fleck. But his ideas are just that, ideas. There are no studies or data. It takes an obvious situtation – we all are, to some degree, conditioned by our education and social backgrounds – and makes the case (to put it crudely) that science is nothing more than the musings of a bunch of dead white guys (or Anglophone-Capitalists). But I still stub my toe against the door jam if I’m careless…
What is an HIV/AIDS denier? Or HIV/AIDS denialist?
Peter Duesberg is a fine scientist, I have read his book and examined some of the scientific papers upon which it is based. From the CDC (Center for Disease Control) in Atlanta I have requested the scientific papers that prove the causal relationship between the HIV retrovirus and the IMMUNODEFICIENCY SYNDROME commonly known as AIDS. They have never sent even references to the peer-reviewed primary scientific literature that establishes the causal relationship because they can’t. Such papers do not exist.
I have seen all four of the films made by Coleman Jones and colleagues in Toronto. Film #3 in the series is most telling. Although no strong evidence exists for any simple causal relationship what is clear is that the HIV claim is erroneous by the standards of microbiology and virology.
When I saw the glowing review of George Miklos, a colleague and a fiercely honest scientist, of Harvey Bialy’s book on the scientific life of Peter Duesberg I bought and read Harvey’s book. I have also read Celia Farber’s superb article in the Lewis Lapham “swansong” issue of Harper’s magazine, last March, I believe. Rebecca Culshaw’s paper on why she quit AIDS statistical research and Dr. Geschachter’s unpublished ms about African AIDS, accepted by the editor and then rejected both substantiated my reluctance to accept the glib “HIV/AIDS” term. I found all of these readings far more convincing than any literature proported to show a HIV-AIDS causal connection.
I heard a talk by a “medical scientist” from the Harvard Medical School at a meeting at Roger Williams Univ in Rhode Island from a supposed expert who attempts to design an HIV vaccine. He claimed the HIV virus mutates a billion times in 48hours. It became clear that the HIV virus has no clear identity. The HIV tests, nearly always positive for pregnant women, that vary significantly in the US, Europe and Australia are particularly disturbing. My son-in-law, James di Properzio spent several months researching this story for the Common Review (the Great Books Foundation in Chicago). His findings were consistent with Celia Farber’s and after encouragement from the editor the board reviewed and rejected his draft.
“Science is the search for truth” said David Bohm, “whether we like it [the truth] or not. From my readings, discussions with knowledgable scientists close to the story, I simply conclude, as does Kerry Mullis, the Nobel Lauriate who wrote a foreword to Duesberg’s classical work that there is no evidence that “HIV causes AIDS”. I have no special expertise. I simply seek the evidence for scientific claims, especially when they have dire consequences for the science itself and the treatment..not just medical..of so many people.
I have observed that the closer one comes to the study of humans the shoddier the quality of the scientific evidence. Maybe that is one of the reasons that I work with bacteria and protoctists (the eukaryotic microorganisms and their immediate descendants exclusive of plants, animals and fungi). The vast majority of these are harmless to human health.
Although I have written about the natural history of the anthrax bacterium, Beethoven’s and Nietzsche’s syphilis and the work of Hentry Taylor Ricketts with insect-borne pathgens (eg.g, ticks carrying Rocky Mt Spotted fever), in general I avoid the last 3 million years of evolution and any other studies thatrequire detailed knowledge of mammalian, including human, biology. Why? Because political bias, hearsay and gossip are inevitable whereas in the first part of the evolution story (from 3800 until 3 million years ago) politics intervenes far less obtrusively. In pursuit of the story of life and its effects on planet Earth one can be more honest if the earliest atages of evolution are the objects of study.
And this way I can lay low and not be “name-called” (i.e., “denialist”) because I ask hard questions and require solid evidence before I embrace a particular causal hypothesis. Indeed, is not my attitude of inquiry exactly what science is about?
Do you believe that HIV patients whose disease is in remission would find it safe to stop taking their anti-retroviral drugs? Would you encourage them to do so?
Make that “AIDS patients”, sorry.
Do you believe that anti-retroviral medications should be made available as a priority for AIDS patients in the developing world?
As a (male Caucasian) Anglophone zoologist, I’d like to apologize for my “thought-style.”
It seems to me like requiring evidence of a causal relationship between HIV and AIDS is a far cry from making treatment or policy recommendations.
If AIDS isn’t caused by HIV, then what would be the cause of AIDS?
On what basis, then, could you ethically prescribe expensive drugs with potentially serious side effects?
Ethically, the question is one of harm and harm reduction. Even if one doesn’t know how the treatment works on a molecular biological level, if it is effective in reducing the harm to or suffering of the patient, it is preferable to no treatment at all. The key to this, or the treatment of any serious illness, is that both physician and patient be fully informed.
Ultimately, though, this seems to me to be a different question than “what causes AIDS?” The search for causation, and thus a cure, should never be perceived as antithetical to the treatment of the symptoms of those who suffer from a disease. As the old saying goes, we musn’t let the perfect be the enemy of the good.
What’s your explanation for the dramatic effect of anti-retroviral cocktails on HIV progression? Some of them (like the protease inhibitors” are pretty highly specific agents. Just by accident they happen to work?
A couple of additional points to ponder re: AIDS and HIV. First, by every formal and rigorous virological test (including the ability to prepare infectious clones using recombinant DNA techniques), immunodeficiency is a disease caused by close relatives of HIV in simians. The cause-and-effect are beyond question. Second, anti-viral therapies for humans include agents that target the HIV protease. These therapies work, and their targets (the viral protease) cannot be mistaken for other nebulous agents of disease.
Given these (as well as thousands of other) considerations, it seems pretty far-fetched to hold to the view that HIV does not cause immune deficiency in humans.
My readings of Margulis’ publications suggests that much of what she writes about “neo-Darwinism” and current evolutionary thought is directed toward inducing polarization. From my perspective, it appears that she does this to enhance the apparent contrast between current thought (which is really a pretty broad spectrum) with her ideas about symbiogenesis. But when the dust settles, I’m not sure the positions are necessarily as diametrically opposed as suggested.
I wish she hadn’t begun her discussion here by invoking “world views”. Biologists are a pretty diverse group and not as monopolistic in their approaches as alluded. Again, the decision to begin the discussion in that way is intentionally polarizing.
Dr. Marguis’ statement really doesn’t state anything concrete. As a geologist I agree that interpretations of evolutionary drivers and patterns too frequently neglect to consider geologic factors – tectonic factors in particular.
My question to Dr. Margulis is: How, specifically, does a newly identified transitional species such as Tiktaalik roseae render a gradualist interpretation less and less valid? Perhaps more specifically, how does its existence make any other interpretation MORE valid?
I would argue that, unsubstantiated, the claim that evolutionary biologists have an ‘anglocentric, capitalistic bias’ amounts to little more than an ad hominen. I agree with Chomsky on this one (this is a rare occurence!); such a claim is analogous to the Nazi claim that much of the physics of Einstein et al was ‘Jewish Science’.
Of course, no one today (and I’m sure least of all Dr. Margulis) would make such a claim, but stating that a science = western, white middle-class male science is a dubiously similar claim. Hopefully, Margulis will back up her claims of such preconceptions biasing scientific thought; otherwise such a blanket dismissal appears highly dubious to me.
“The HIV tests, nearly always positive for pregnant women, ”
This claim is false. On the contrary, HIV testing in pregnancy, combined with anti-retroviral therapy has greatly cut the incidence of mother to child transmission.
http://www.annals.org/cgi/content/full/143/1/38
and
http://query.nytimes.com/gst/fullpage.html?res=9E03E0DE153BF933A05752C0A9639C8B63&sec=health&spon=&pagewanted=1
Lynn:
Do you have any specific examples of “neo-Darwinists” “ignore(ing) the non-zoological components of evolutionary science”. I can see your point that most of the people working on this are in fact biologists, but I think that you are remiss in stating that they ignore other fields. In fact, if evidence from other fields contradict biological work (say, fossils), then I doubt that it would become established as having scientific merit. Scientists work within a framework which has as its skeleton all the other branches of science. So the second part of my question is this:
You seem to be very pro-specialization in science by (to paraphrase)stating how people can only understand tiny, narrow fields, and their work is only valid within a tiny slice of specialized knowledge. However, you then criticize neo-Darwinian biologists for being too narrow in their thinking! Isn’t this a good justification for scientists being less narrow in both training and focus?
Ok so according to wikipedia (yes I realize to take it with a grain of salt, and please corect me if I’m wrong): She believes that the driving force behind genetic change is the exchange of genetic material between cells and bacteria and viruses instead of random mutation.
I’m curious to know how the first sentence doesn’t make the second one rubbish. Actually, I think it does severe damage to the whole paragraph.
[dons lab coat]As a scientist, I think the whole essay would have been improved by the addition of some evidence for the claims of bias in evolutionary biology.[/dons lab coat]
Bob
Here is some new science.
http://www.cbc.ca/technology/story/2007/03/09/science-nervessound-20070309.html
Sounds like the Professor really prefers literary theory to science.
“And this way I can lay low and not be “name-called” (i.e., “denialist”) because I ask hard questions and require solid evidence before I embrace a particular causal hypothesis. Indeed, is not my attitude of inquiry exactly what science is about?”
That depends on whether those questions are really honest, solid science ones, or whether they are straw man literary theory puffery like accusations of ‘anglocentric, capitalistic bias.’
“From my readings, discussions with knowledgable scientists close to the story, I simply conclude, as does Kerry Mullis, the Nobel Lauriate who wrote a foreword to Duesberg’s classical work that there is no evidence that “HIV causes AIDS”.”
According to his popular book (Dancing in the Mindfields), Kerry Mullis also believes strongly in astrology and that a raccoon spoke to him in his backyard, possibly serving as an agent for aliens communicating with him. Are you suggesting that just because he is a Nobel Lauriate that we should take these ideas more seriously as well?
Name dropping is not the same thing as a good argument.
Dr. Margulis,
The new buzz is about evolution having “strategy” and “plasticity” as functional tools, such as Lynn Caporale’s Darwin in the Genome and your own attention on merged organisms. This imbedded tooling – tacitly leads back to thinking of Lamarckian concepts, similar to what was entertained by Darwin. Can you comment on this potential of an indirect “Lamarckian Leak” into the genome and the work of Ted Steele?
As an economist who dissents from the prevailing economic paradigm of reducing all economic questions to “cost-benefit” calculations, I’m intrigued by Professor Margulis’ views of the extent to which neo-classical economics has driven evolutionary biology. I say intrigued but not entirely convinced.
It also strikes me that the problem is not so much the application of cost-benefit calculations to biology, or the calculation of optimizing strategies for bacteria-but the application of these ideas to decision making strategies of conscious, purposeful agents (human beings).
I will readily agree that our “language structure” limits us to think in certain ways, right down to currency metaphors used to describe ATP. Maybe if we lived in a different kind of society we would think of different metaphors. But we don’t.
To what extent have cost-benefit models really occluded our understanding of evolutionary biology? IMO (as a mostly observer in this matter) not very much.
It’s very unlikely that “most people interested in evolution live in an Anglophone-capitalist culture” is true.
Dr. Margulis made her name by identifying symbiosis as a primary (if not the primary, in her mind) means by which evolution occurs.
Margulis has demonstrated that eukaryotes evolved when prokaryotes formed symbiotic systems. Instead of competition, it was a love fest.
When HIV enters a cell, the result isn’t symbiotic, much less a love fest.
Looks like someone’s paradigm is getting in the way…
“Margulis has demonstrated that eukaryotes evolved when prokaryotes formed symbiotic systems. Instead of competition, it was a love fest.”
That isn’t anthropomorphizing things a little much? Did the organisms really “love” each other and want to “help” each other? Is salmonella trying to “help” peanut-butter purchasers but just not getting things right?
Worse, everything involved in symbiosis can be translated directly into neo-Darwinian terms without even breaking a sweat (heck: treat each of the two organisms in some joining as if they were simply environmental conditions from the point of view of the other, and the story is no different than adaptation in general). Neo-Darwinian ideas can’t account for “cooperation???” Pifle.
To plunge: precisely.
I agree with windy.
After all, numerous scientists from Communist China have made numerous, tremendous contributions to Biology and Paleontology.
I’m not sure I get the whole “neo-Darwinists” “ignore the non-zoological components of evolutionary science” but I can see a danger to ignoring Endosymbiotic theory and the way genes can cross into other organisms. There is a lot of genetic engineering going on today and they are finding the new genes in plants they didn’t put them in.
Later I’ll google and search for news stories that illustrate this.
It may be that we can’t genetically engineer just a plant and that to genetically engineer anything risks genetically altering the whole biosphere.
When Darwin’s work was first published it was generally acknowledged that he was influenced by Adam Smith’s English capitalist economics. Even Karl Marx noticed this – interestingly he felt that such an analysis was more correct in the sphere of biology than political economy :) I see this as a historical statement of fact – not some “post modern” revisionism as some here seem to be seeing it. The only problem is when those assumptions and how they can colour how evolutionary theory (or any science) has developed are not recognised. It’s the assumptions we make that are not recognised that affect us the most and often come back to haunt us – in that context it seems a bit silly to say she can’t be right because “most scientists” have never noticed such things.
I have to say the attempts to lump her in with the ID/Creationist rump are rather saddening (ironic though that they do the same thing). Lynn Margulis is an evolutionary theorist and not a Creationist. She’s simply developed a model that is radically different from the Neo-Darwinian one but still acknowledges the foundation of Darwin’s work. In her view what Woese refers to as a “Pre-Darwinian” threshold is not a threshold at all – symbiosis, lateral exchange of information and cooperation are seen as having continued to be the central processes in the development of evolutionary change and variation – she’s not completely rejected notions of competition existing on some levels of analysis but to her symbiogenetic explanations are often more significant, especially in the larger changes (such as between higher level taxa). Of course this is exactly why she argues the too often unrecognised “bourgois” subtext of much of Neo-Darwinism – which is very much based on competition and stuggle to the nth degree (even “selfish” genes if you take it as far as Dawkins does) is so important and a vital issue to debate.
Not saying I agree entirely on HIV/AIDS – I’ve always felt myself the connection was clear enough (but would be interested in reading some of Lynn’s sources myself) but I also think Lynn is making some important points about the scientific method, not HIV/AIDS per se as far as I can see – seems to me too many people are jumping in on that one issue without recognising the context – ironically this was her first point and concern about such tendencies in internet debates.
I did a google, but I haven’t found the news stories I remember reading, but I found some new stuff I’m just starting to read:
http://www.gefreemaine.org/article.php?story=20060120223503466
http://www.greens.org/s-r/26/26-16.html
Look for biotech contamination, biotech pollution, or genetic trespass.
There may be a post on this on my blog in the near future:
http://normdoering.blogspot.com/
I can’t sum it up here today.
I never formally studied population genetics, but the analysis of alleles in a population never rang true to me as to what evolution is really about. The neo-Darwinian synthesis is a beautiful mathematical construct, but does it truly reflect the complexity of how the world of living organisms changes over time. That is a valid question to ask.
One thing should be clear. Challenging one mechanism or another does not challenge the fact of evolution. In any dialog scientists will argue with one another and take opposing views as part of the ‘search for truth”. They will be rude, inflammatory, and worst at times, but in the long term, the facts eventually winnow themselves out from the arguments. That the enemies of scientific thinking, like the proponents of ID, make use of the arguments of one side or other is irrelevant to the debate itself. By all means challenge ID and like nonsense, but not at the cost of limiting the debate.
As for the Neo-Darwinian synthesis, we are no longer operating with the understanding that one gene equals one protein, which was the context of the old synthesis. What is an allele in a post-transcriptional nucleus, where different proteins are spliced from the same gene or RNA regulates what is ultimately translated in unexpected ways? Why build the story of evolution around point mutation when whole genes and parts of genes can be moved about deleted or duplicated? Evo-devo begins to look at evolution in this new light of information, but still does not include the wealth of new information or encompass what the new synthesis will look like.
So on that score, Dr. Margulis was correct, maybe. But more to the point is “The new synthesis is dead, long live the new synthesis” and her contribution is always welcome.
Dr. Margulis discusses the communication of concepts in science to the non-scientist. The more specialized a concept is, the more externally incomprehensible the language about it has to be, beginning with specialized use of common words (Evolutionary Biology’s “fitness” as opposed to the broader English “fitness”), moving on to esoteric terms or neologisms (methylated genes, which is not mentholated jeans..) and eventually to arrive at mathematical formulas. Precision or accuracy in description within science suffers with increased ability to communicate to the outside world. This is the basis for a widely believed explanation for why scientists can’t really get their ideas out. Dr. Margulis makes this assertion and adds to it the difficulty of science writers being able to handle a diversity of fields, etc.
As an example, consider the following statements about the same thing (The formula is made up though loosely related):
In lions, the female does almost all the hunting, but the male has first access to the kill and the others will eat only after he is finished and allows them to do so.
Lionesses benefit indirectly from scavenging or scrounging by males because this keeps the males fit and healthy, and thus makes a pride takeover less likely.
A = E[sin(2Theta)-2E(sin(T)cos(T) is maximized when
cos(T) = cos(2T) + [sin(T)sin(t)]/cos(T)
The first statement could be interpreted as a statement about family values in lions. The second statement is more accurate but incomplete and includes an element of teleology and intentionality that is irrelevant to the argument, and probably wrong. It also has a funny use of the word “fitness.” The thirds statement stands in for a formula used in dynamic optimization modeling that was part of the study done by Packer et al that has helped to clarify certain aspects of lion social behavior, including this one. Only the mathematical model is fully accurate and correct, but only a small number of people can appreciate it. The most accessible statement above is terribly misleading and inaccurate to the extent that maybe it is better in this case to leave the public ignorant about lion behavior and just keep our scientific mouths shut.
This – this description of the difficulties of communicating science – is an attractive model but I think it is wrong. It is not a good description of the relationship between scientific knowledge and public discourse. Not only it is wrong but it is also mainly an excuse scientists use to explain … and avoid blame for … the fact that they (the scientists) have not made themselves heard by, let along understood by, the public.
Dr. Margulis very significantly and I think correctly points out that there are biases in science, and she specifically mentions Anglophonia, which means mainly communicating in English. She mentions the capitalist model and important concepts such as “cost-benefit” and “competition vs. co-operation” as parts of what I assume she feels is a limited and limiting approach to doing things and describing what we are doing.
I am a scientist who is also an anthropologist, so it is not surprising that because of my training and experience, I heartily agree with this.
However, I think this second point of Margulis … that we tend to work in a biased framework … should be turned back onto the first point … a kind of Heisenberg Principle of explanation (in order to really explain it to ourselves we must obscure it for others).
It is simply not true that all (or even most?) important scientific concepts can be, need to be, or are best expressed as formulas. Endosymbiosis comes to mind! There are plenty of ways to use mathematical modeling to demonstrate aspects of endosymbiosis, to make predictions, etc. But the most accurate, least wrong, “best” (however you want to put this … in Kiswahili we would say “safi na haki,” roughly clean and true, and in German there is probably a word like Komplettenexatkebeschreibungwarheit) and nontrivial description of endosymbiosis may well be verbal, even among specialists (but verbal in what language???).
There are some concepts in science that are to falsehoods what flypaper is to flies. For example, describing any kind of social behavior theory or observations (for any taxon, investigating any theoretical area) to the average person is a minefield. Indeed, it may be that the best way to describe many concepts in socioecology involve wading in and grabbing the listeners misconceptions and wrestling with them directly as a way of getting a more subtle point across.
Other concepts are virtually incomprehensible from the perspective of our size (tens of kilograms) and our environment (in terms of gravity, electromagnetic radiation flux, etc.). I’m thinking here of quantum mechanics. The best way to describe certain aspects of quantum mechanics to get even a glimmer of understanding may well be to use these biases (A photon is like a teenager …. they are constantly flitting back and forth between electrons, which are their friends houses…). Photon behavior can probably only be understood by lerning the math, perhaps leraning Feynman diagrams, etc. But a human-sociological model could work, and we do not risk the learner getting strange ideas about the family values of bosons and quarks, as they would if the subjects of the description were fellow mammals.
Other concepts are very well matched to the cost benefit model of Angophone capitalism. Why would a female red deer benefit by biasing offspring sex? “Well, suppose your rich Aunt Tillie dies and leaves you with a thousand dollars and you now need to decide to buy one thousand lottery tickets, or to invest it in a conservative mutual fund….” By the end of the Aunt Tillie parable, most people get Trivers Willard dead on, in my experience. Trivers Willard is probably a good example of a capitalistic cost benefit model that very accurately and effectively describes and predicts things in nature, and by using a finance based metaphor we can avoid too much anthropomorphism, because normal humans “get” cost benefit but they do not “understand” finance.
I assert that there is no consistent or useful correspondence between some idealized series of specialization, detail, accuracy and truth in science, and difficulty in explaining the science outside of the area of specialty. Instead, the relationship between “truth,” understanding, explanation, and scientific background (or lack thereof) is complex. There are scientific concepts, I believe, that can be explained easily with good results, there are those that can be explained easily but with bad results if you do it wrong, and there are those that can perhaps only be understood by becoming a specialist, or nearly so.
Now a quick word about science journalists: I think the problem here is not so much the nature of science vs. culture, but simply of quality. I think that most science journalists suck at what they do. Others are unbelievably good at it. There are all sorts of possible reasons for that but this is not the place for that discussion.
Yes, there may be a systematic relationship between internal professional truth and understanding and external explanation (though as I say it is non-linear and complex) on one hand and science journalisms’ failings on the other. But I think the overwhelming variation in quality is at present the biggest factor. We need to work past that first, then we can start to observe the relationship between how science works internally and what it looks like from the outside.
Dr. Margulis, thanks for taking the time with this blog tour!
Cheers,
Greg Laden
Monad: “Lynn Margulis is an evolutionary theorist and not a Creationist.”
I think most people here know that. The problem is that she is remarkably, tone deaf about how she phrases her criticisms, making them ripe and confusing fodder for the ID movement.
Remember that intellectual conservative site PZ linked to?
http://www.intellectualconservative.com/2007/02/27/rational-evolutionary-hypothesis/
Check the comments. Why, it’s Dr. Lynn Margulis, apparent champion of the idea that there isn’t good evidence for evolution, and that any idea that her ideas are compatible with evolutionary theory is an “absurd rationalization.” And that’s certainly how it must sound, given how over the top and polerizing her rhetoric is. Which is especially odd given that plenty of “Neo-Darwinists” seem very excited by how neat both her theory and her struggle to get it recognition were.
Or you could look at the literature and find out that such things are tested, not assumed.
Keep in mind that rhetorical uses of terms like ‘darwinism’ or ‘neodarwinism’ are beside the scientific point. Margulis is said to enjoy casting herself as the radical, but it can become too much of a habit. Also take the statement about Mendel with a grain of salt.
Surely symbiosis can be discussed without implying that everyone but oneself is scientifically and morally deficient.
It’s ironic that the champion of cooperation in nature is such a non-exemplar :)
I agree with Unsympathetic reader‘s interpretation, specifically: “My readings of Margulis’ publications suggests that much of what she writes about “neo-Darwinism” and current evolutionary thought is directed toward inducing polarization.”
Insofar as she has stated her ideas and criticisms, here and in the chat, I don’t see much of an incompatibility with the modern evolutionary synthesis. She herself has reiterated her acceptance of the basic fundamentals of evolution, which of course is the only evidence-based scientific position to take on the matter.
However, her criticism that the modern synthesis is too focused on zoology and genetic mutation, while containing some truth, does not in any way invalidate the modern synthesis. There is not a huge paradigm shifting waiting in the wings here, but rather just another voice that has something to add to our understanding. Unfortunately, her rhetorical tone makes it sound as though her work in microbiology and symbiosis is contradictory to the good zoological and genetic work that has been done, when it’s quite clear to me that her work is in fact entirely complementary. The paradigm doesn’t have to shift so much as shuffle over a bit.
“They rarely acknowledge that their theoretical frames derive from an Anglophone-capitalist model”
Lewontin also pointed this out; the assumption is that because of this (assuming it the case) Darwinism – and particular intellectual heirs like the Modern Synthesis and sociobiology/evolutionary ecology – are somehow profoundly theoretically and philosophically tainted, unless we recognize and exorcise capitalism and bourgeois individualism from our theory.
This charge against ‘mechanistic,’ ‘reductionist’ ‘atomized’ and adaptationist biology as opposed to ‘integrated’ and holist biology is the biological/natural philosophy side of the Continental vs Anglo-American intellectual divide, which carries over into politics, economics, and philosophy. Continental (often, Franco-German) thought is holistic, organicist, and collectivist, while Anglo-American thought is individualistic and bourgeois. The Continent aspires to the heroic and meaningful, while Anglo-America is supposedly money-grubbing and banal. (The ‘nation of shopkeepers’ charge.) It goes back to the Romantic anti-Enlightenment reaction on the part of influential figures like Rousseau, Hegel, and Goethe.
There might be something to the Continental-holistic critique of neo-Darwinism. The problem is, a lot of really noxious ideas emerged out the anti-bourgeous/individualist worldview. Haeckel’s Monism, to name one example. And another, obvious, glaring example.
I have a better idea. Instead of dismissing one or another school of thought as fatally ideologically and philosophically tainted, why don’t we attempt to synthesis the best of all schools of thought – a true synthesis of ‘reductionist’ evolutionary ecology and ‘holistic’ developmentalist-structuralist approaches?
Also see:
Anne Harrington, ‘Reenchanted Science’
http://tinyurl.com/2ldon5
Gilbert and Sarkar 2000. Embracing Complexity: Organicism for the 21st Century
http://tinyurl.com/2ka93c
Let me note that I am more receptive to many of Margulis’ ideas than are some others on these threads – not just the widely accepted endosymbiont origin of the eukaryotic cell, but also Gaia and genome acquisition. However, Margulis posits false choices between approaches that are inappropriately characterized as mutually incompatible. And my acceptance, or least interest, in some of her heterodox ideas finds its limit in her HIV ‘skepticism,’ which I find saddening to say the least.
The opening of these remarks by Margulis seems to make some helpful points, especially about science’s concern with details, which makes distortions and imprecision inevitable when explaining science to non-specialists. My father was very struck recently by an American Scientist article on imprinting of genes in placental mammals– the details of how these genes are silenced, and how this undermines the usual advantages of having two copies of each gene are a fascinating correction to the usual story of inheritance. But the subsequent vague remarks about neo-Darwinism are not very illuminating– perhaps because I just don’t get the context, but I suspect that there is less here than meets the eye. There have been many attempts to tie scientific conclusions to social and cultural causes (Bloor, Barnes and the so-called ‘strong programme’ in sociology of science come to mind). But when it comes to the details, evidence and calculations explain a lot more of what goes on in science than ideological precommitments do. Does Dr. Margulis claim the mathematical foundations of the modern synthesis really represent scientific failure or a ‘wrong path’ for biology? I hope not…surely at worst they need to be supplemented with more details and ideas, rather than treated as the final word on evolution.
Lynn points out that the Internet amplifies miscommunications and that the use of “sound bite-hype is far more useful to those who assert religious truths and would banish authentic science from the public sphere than to the scholar or scientist.” There is truth in that statement….and yet…
I opine that the use of sound bite hype can be used to further any argument on any side in the public arena if action is needed to ameliorate some illness or some misunderstanding. And if scientists of prominence such as Lynn cannot use it well, then we will be subsumed by those protagonists who do use it to their advantage…because the masses only read the headline…and hear the sound bite.
Lynn…Lyme patients still need your input into the peer reviewed literature on Bb spirochetes and their ability to persist against all odds.
Strikes me as ridiculous. How did they try to measure the heat? Why do they think sound would not generate heat — maybe even more heat? What do they think all those well-researched sodium, potassium, calcium and chloride channels are for? They have overlooked decades of research, and are arrogant enough to believe that everyone is just as ignorant as them. The hallmark of pseudoscience.
Strikes me as ridiculous. How did they try to measure the heat? Why do they think sound would not generate heat — maybe even more heat? What do they think all those well-researched sodium, potassium, calcium and chloride channels are for? They have overlooked decades of research, and are arrogant enough to believe that everyone is just as ignorant as them. The hallmark of pseudoscience.
Yeah, and speaking as one of many neuroscientists who has stuck an electrode in a cell and an axon and recorded electrical impulses, and who has read the biophysics literature and knows the details of channel activity and gating currents, and can derive the Nernst equation…that is a really dumb idea. Do they even have a mechanism for transducing a soliton wave into transmitter release? Or are we going to get rid of the concept of neurotransmitters, too?
At least two… no, three.
At least two… no, three.
Oh yes, they don’t mention where the measured electricity comes from, do they? (Thanks for mentioning the most obvious. It’s half past 2 at night over here, I can’t think anymore.)
You scare me.
Oh yes, they don’t mention where the measured electricity comes from, do they? (Thanks for mentioning the most obvious. It’s half past 2 at night over here, I can’t think anymore.)
You scare me.
“The HIV tests, nearly always positive for pregnant women”
This is a claim that comes straight out of “rethinker” literature. It is not true. There is a small increase in the false positive rate in pregnant women but this amounts to only a fraction of a percent of those testing and certainly nowhere near the 100% that Lynn Margulis would have us believe.
This tells me that Lynn Margulis is getting her factoids from “rethinker” literature and not from peer reviewed science.
She certainly appears to be familiar with the “rethinker” literature but claims to be unaware of the scientific literature providing evidence that HIV causes AIDS.
Great to have Dr. Margulis here. I’ve always respected her work, and literally worshipped (as much as an aetheist can worship) the work of her deceased husband, Carl Sagan.
But, I am unfamiliar with the argument about AIDS. I thought this was a rock-solid issue (virus causes it). But, it seems as though a lot of right-wing homophobes seized on the issue to stigmatize gay men. Then, pharmaceutical companies (also a tool of the right-wing) seized on the issue to market and sell a lot of drugs.
I do remember when Dr. Peter Duesberg of UC Berkeley, a molecular biologist, (don’t know his view on evolution) wrote a paper in Cancer Research, challenging the theory.
Unlike those jerks at DI, this was peer-reviewed work. Is this what Dr. Margulis is referring to?
But, it seems as though a lot of right-wing homophobes seized on the issue to stigmatize gay men. Then, pharmaceutical companies (also a tool of the right-wing) seized on the issue to market and sell a lot of drugs.
Are you saying that all scientists involved in HIV/AIDS research are right-wing homophobes?
Duesberg’s hypothesis that lifestyle factors are responsible for AIDs rather than a virus appear to be more homophobic. His idea that drug use causes AIDS firmly puts the blame on the victim.
Raphael Lombardo was featured in Duesberg’s books as evidence that if you are HIV+ and don’t take recreational drugs or antiretrovirals that you won’t get AIDS. See this article
However, Raphael died shortly afterwards from AIDS despite not taking drugs or antiretrovirals. Duesberg’s recent response was to accuse Raphael of lying about not taking drugs. According to Duesberg it is their own fault that they die from AIDS because they take drugs. If they say they don’t take drugs and still die then they are lying.
I am afraid that Margulis’ position on AIDS demonstrates the dangers of being a maverick on one issue and then being vindicated. If you aren’t careful you can end up supporting maverick positions for which there is no evidence. Other examples are Fred Hoyle’s championing of panspermia and Linus Pauling’s vitamin C pseudoscience.
Mr. Noble. Perhaps you would enlighten us on the exact cause of death of the Raphael Lombardo case, as AIDS is not a cause of death. It simply defines a syndrome of immune suppression. And ONLY defines that syndrome
providing that one of the proven to be faulty HIV tests has shown as positive.
Until such time as you present us with first hand knowledge of what this individual died from in exactitude, your comment must be construed as meaningless. If you do show us a disease caused by a known pathogen, then the pathogen itself is obviously the cause of the disease. What other effectors could have contributed would only be known to those near and dear to the deceased.
I would hope you are not one of those right wing homophobes mentioned just above? There is certainly nowhere in any of Duesbergs publishings where he “blames” anyone for taking drugs.
Mr. Noble, do you happen to think illicit drug use is somehow beneficial to health and well being, for some strange reason?
Raphael’s sister has described how he succumbed to Kaposi’s sarcoma, MAC, systemic candiasis and PCP before finally dying. These are all rare opportunistic diseases that are classic manifestations of HIV/AIDS. You can play as many word games as you want with “syndrome” but it still remains AIDS.
Duesberg’s basic message is that HIV is harmless. If you don’t take drugs then you won’t get AIDS. After Raphael Lombardo died with the classic symptoms of AIDS Duesberg accused him of lying about not taking drugs. I find it disgusting that Duesberg used Lombardo as an anecdote supporting his theory until he died. After he died he was supposedly a liar. In my eyes this demonstrates a contempt for the people who die from AIDS. Blaming AIDS on lifestyle factors such as drugs does blame the victim.
Implying that I advocate illicit drug use is a silly logical fallacy. In fact Duesberg accused Michael Ascher of exactly that after Ascher published a paper that demolished Duesberg’s theory. Somebody saying that illicit drugs cannot acount for AIDS does not imply that they think illicit drugs are good for you or without harmful effects. To imply this is frankly a silly rhetorical game.
It seems that Lynn Margulis is being feted as the most recent champion for the HIV “rethinkers”. What she has written so far demonstrates that most of what she knows about the subject is gleaned from reading Bialy, Duesberg and the other “rethinkers”. As she repeats the baseless claim that almost all pregnant women will test HIV+ she does not appear to have applied any skepticism to what she has read.
I am afraid that writing to the CDC and asking them to send her “proof” that HIV causes AIDS would probably have been filtered off into the rest of the junk mail they receive. It has to be one of the most ridiculous arguments used by “rethinkers”.
Lynn Margulis wrote:I heard a talk by a “medical scientist” from the Harvard Medical School at a meeting at Roger Williams Univ in Rhode Island from a supposed expert who attempts to design an HIV vaccine.
It appears that the “medical scientist” is Norman L Letvin who gave the talk immediately prior to Margulis at the conference in question.
I wonder what he thinks of being labelled a “medical scientist” or a “supposed expert” from an individual who says she has no special expertise in the field.
Margulis would also be advised to look at Letvin’s work that uses a SIV/HIV chimera, SHIV89.6P, to produce AIDS in macaques. This destroys Duesberg’s main claim that a retrovirus like HIV cannot possibly cause AIDS.
I’d appreciate comments on this, not because I think it’s controversial but for your opinion on how well these ideas have settled in.
Found while trying to explain the “plankton cooled a greenhouse” article about the termination of the PETM temperature spike, PDF file is
http://www2.unil.ch/lpc/images/docu04/gene/plastidevolution.pdf
TRENDS in Genetics Vol.18 No.11 November 2002
Recycled plastids:a ‘green
movement’ in eukaryotic evolution
John M.Archibald and Patrick J.Keeling
From: http://scholar.google.com/scholar?num=100&hl=en&lr=&newwindow=1&safe=off&q=cache:JnwBbVaIPD8J:www2.unil.ch/lpc/images/docu04/gene/plastidevolution.pdf+white+cliffs+of+Dover
“… Most photosynthetic dinoflagellates contain a three-membrane plastid with the
characteristic pigment peridinin. However, some dinoflagellates have substituted
their peridinin-containing plastids with a new one in a process referred to as tertiary
endosymbiosis. Dinoflagellates are known to have acquired tertiary plastids from
cryptomonads, heterokonts and haptophytes, as well as a second secondary
plastid from a green alga [a,b]. Dinoflagellates are truly the algal experts at plastid
acquisition, raising an intriguing question: has a dinoflagellate ever substituted its
peridinin-containing plastid with another peridinin-containing plastid from an
unrelated dinoflagellate?”
and
“How many secondary endosymbioses?
With the realization that secondary-plastid-
containing algae constitute a large proportion of the
diversity of photosynthetic eukaryotes comes an
important question: how often have these mergers
happened? The integration of endosymbiont and host
is an immensely complex series of events that has a
formidable effect on both host and endosymbiont. It
involves massive transfers of DNA between genomes,
the development of a sophisticated protein-targeting
machinery and a substantial reorganization of core
and secondary metabolism. Untangling these events
and understanding their effects on eukaryotic
evolution requires fundamental knowledge of which
algal lineages arose from the same endosymbiotic
partnerships and which arose independently.”
“I am unfamiliar with the argument about AIDS. I thought this was a rock-solid issue (virus causes it).”
Let’s ask the experts:
“…the presenting plasma HIV RNA load predict[s] no more than 10% of the observed CD4 cell loss in patients with chronic untreated HIV infection… Twenty-five years into the HIV epidemic, a complete understanding of what drives the decay of CD4 cells – the essential event of HIV disease – is still lacking…. The puzzle of HIV pathogenesis keeps getting more pieces added to it… Future improvements in the treatment of HIV infection and AIDS may result from improved understanding of the 90% of CD4 cell depletion that remains enigmatic.” — Henry WK, Tebas P, and Lane HC, 2006. “Explaining, Predicting, and Treating HIV-Associated CD4 Cell Loss: After 25 Years Still a Puzzle”, JAMA, 27 September 2006; 296: 1523-1525.
“The rate at which an untreated HIV-positive person’s CD4 cell count is declining is a poor predictor of the risk of AIDS or death in individual patients the Fourteenth Conference on Retroviruses and Opportunistic Infections was told this week… medium-term baseline CD4 decline was a very poor predictor: it only predicted 2.9% of the time to AIDS… This means that medium term CD4 decline – the quantity Rodriguez said was poorly predicted by viral load – is itself a useless predictor of progression to AIDS…” — Cairns, Gus, 2007. “CROI: Rate of CD4 decline is a poor guide to the risk of AIDS, say investigators”, 2 March 2007, aidsmap news.
“The pathogenic and physiologic processes leading to AIDS remain a conundrum.” — Grossman, Z., 2006. “Pathogenesis of HIV infection: what the virus spares is as important as what it destroys” PubMed”, Nat Med. 2006 Mar; 12(3): 289-295.
Mainstream researchers now admit HIV science is in a state of confusion. And epidemiology remains the only evidence for the HIV hypothesis.
“I do remember when Dr. Peter Duesberg of UC Berkeley, a molecular biologist, (don’t know his view on evolution) wrote a paper in Cancer Research, challenging the theory. Unlike those jerks at DI, this was peer-reviewed work. Is this what Dr. Margulis is referring to?”
This is one of the papers challenging HIV, yes.
Other papers you may be interested in reading:
http://www.reviewingaids.org/awiki/index.php/Template:Documents
I would hope the readers of this blog would take the time to examine these papers with an open mind, before being “saddened” by Margulis’s “denialism”.
Hank R – here is a nice article on secondary endosymbiosis confirmed by genome sequencing:
http://www.the-scientist.com/article/display/15509/
Well, I am saddened by her lack of response on this blog to the questions about specific Neo-Darwinian claims that she thinks are unsupported. All we get are second-hand discussions of population genetics. I agree that her statement is completely tone-deaf, and also agree that it is probably already being used in a 15 page “brief” by Luskin et al. That is sad.
But perhaps the lily-white anglophones at the DI will be easy to discourage when it is pointed out to them that Margulis is really only dissing one part of evolutionary theory, and that it happens to be the most mathematical part. Since Dembski et al. are trying to convince the world that math is better than biology at explaining biology, they may not want to agree with someone who thinks that mathematical constructs don’t explain biology at all!
PZ wrote:
“Yeah, and speaking as one of many neuroscientists…”
Why do you always have to be so surly?
I can almost see the sneer.
After having full-blown AIDS and near death, I can attest to the fact that it is very real. What amazes me is that the scientists nor the doctors want to listen to persons such as myself who have beat this disease and without staying on the anti-virals. I guess that we would burst a big hole in all of their theories and they would have egg on their faces and would have to admit that they are not as smart as they think they are.
Many have heard of my story but I repeat it for those who haven’t. I only take low dose Naltrexone, a much safer drug to keep me healthy. I have been off the anti-virals for over a year and my CD4’s are at 86. My blood work has greatly improved since stopping the AIDS meds. I am the picture of health! If I can do this so can others. I tell my story at iuiverse, “Surviving AIDS & Cancer.” My goal is not to argue but to inspire and help others.
Some people are resistant or immune to HIV; some of the genetic factors causing this, especially immunity, are known, and they’re certainly researched. But of course such genetic luck is not something other victims can imitate.
If the claim is that HIV doesn’t cause AIDS, and given what’s at stake if that’s true, then perhaps Dr. Duesberg would volunteer to be injected with HIV as test of the claim?
Also I get a distinct sense (maybe it’s my bias) that PZ is pulling his punches regarding Dr. Margulis’ statements.
I am afraid that writing to the CDC and asking them to send her “proof” that HIV causes AIDS would probably have been filtered off into the rest of the junk mail they receive. It has to be one of the most ridiculous arguments used by “rethinkers”.
Indeed – I would recommend reading Mullis’ forward to Duesberg’s book (but don’t buy a copy, for god’s sake) if only for the entertainment value. Mullis puts forth a hilarious argument based mainly on the fact that many eminent scientists don’t want to talk to him.
Imangining Mullis tracking these people down and accosting them at various meetings, harrassing them with a rather stupid question, and then interpreting their desire to have him go away as vindication rather than as evidence that he’s an annoying tool made me laugh…
“If AIDS isn’t caused by HIV, then what would be the cause of AIDS?”
I can’t speak for Margulis, since I am not her.
However, one hypothesis for which a strong case can be made is that the phenomena being interpreted as “HIV” and “AIDS” are both themselves effects of a common cause — namely, oxidation of cells, brought on by a variety of toxic, nutritional, and mental causes, leading to a disruption in the cellular redox and a shift from Th1- to Th2-dominance among the CD4+ cells. This explains both the loss of cell-mediated immunodeficiency detected by CD4 counts in the circulation, the abundance of antibodies that cause “HIV tests” to react in AIDS patients, as well as the presence of phenomena interpreted as “HIV infection”. The indicated therapy would then be to use reducing agents to halt oxidation of cells and to cease exposure to the oxidizing toxins.
You can find more details at the link I gave above. But in order to wrap your mind around such a hypothesis, you have to get out of the “HIV box”.
“If the claim is that HIV doesn’t cause AIDS, and given what’s at stake if that’s true, then perhaps Dr. Duesberg would volunteer to be injected with HIV as test of the claim?”
Not necessary. Not really scientific, either. But you’re in good company…Richard Horton tried to pull this one (the “self-experimentation” offer) more than 10 years ago. Read Serge Lang’s response:
http://www.reviewingaids.org/awiki/files/NYR5.pdf
“Imangining Mullis tracking these people down and accosting them at various meetings, harrassing them with a rather stupid question, and then interpreting their desire to have him go away as vindication rather than as evidence that he’s an annoying tool made me laugh…”
If it’s such a stupid question, shouldn’t they have been able to come up with better answers than “Why don’t you quote the CDC report”?? Is this the mindset of (young, presumably) scientists nowadays? Back in the day, if a colleague asked you a simple question and you walked away, it was a mark of shame.
“I would appreciate it if Prof. Margulis would clarify her position on the relationship, if any, of HIV and AIDS. There appears to be some confusion on her position relative to this issue due to a review of a book by Prof Duesberg who is a noted HIV/AIDS denier.”
Margulis didn’t review one of Duesberg’s books, she reviewed a biography of Duesberg written by Harvey Bialy:
http://www.reviewingaids.org/awiki/index.php/Oncogenes%2C_Aneuploidy%2C_and_AIDS
Um, thats not really her, is it PZ?
Tell me thats one of Taras Trolls.
A noted Mathematician (real science mind you) worked with HIV models for several years, but recently wrote her dismay that much of the science is pretty much bogus.
Dr. Rebecca Culshaw wrote the piece —Why I Quit HIV. I think this is what Dr. Margulis noted above.
A noted Mathematician (real science mind you) worked with HIV models for several years, but recently wrote her dismay that much of the science is pretty much bogus.
Dr. Rebecca Culshaw wrote the piece —Why I Quit HIV. I think this is what Dr. Margulis noted above.
Published on LewRockwell.com. Right.
Actually, there has been an HIV/AIDS (rethinker/dissident/denialist whatever).Who injected himself with the virus five times over a period of a year and a half.He died of a heart attack, hardly an AIDS defining illness for a man who was 65.
http://en.wikipedia.org/wiki/Robert_Willner
Then you also have Dr. Jeremiah Abalaka, who claims to have created a series of vaccinations for HIV and use himself as a guinea pig.
Willner simply stuck a needle into a HIV+ person and then stuck it into himself. The risk of HIV via a needle stick injury is relatively low – 0.3%. The only thing that Willner demonstrated was a fraction more honesty than Duesberg who continues to make up silly excuses for not infecting himself with HIV.
Several famous scientists, Frank Fenner, Frank Macfarlane Burnet, and Ian Clunies Ross famously injected themselves with myxoma virus, to prove it was not dangerous for humans. Why can’t HIV “rethinkers” do the same?
A noted Mathematician (real science mind you) worked with HIV models for several years, but recently wrote her dismay that much of the science is pretty much bogus.
With all due respect but Culshaw is only a “noted” mathematician in “rethinker” circles. The reasons she gives in that opinion piece for her dismissal of HIV science are just regurgitations of factoids she has read in “rethinker” literature.
For instance she writes: The current testing protocol is to “verify” a positive ELISA with the “more specific” WB (which has actually been banned from diagnostic use in the UK because it is so unreliable).
The Western blot has not been banned in the UK. This is a myth that is only found in “rethinker” websites. Culshaw demonstrates that she gets her factoids from “rethinker” websites rather than the scientific literature. Culshaw makes it clear that it was not her own research that lead her to doubt that HIV causes AIDS but rather the “rethinker” literature.
“Neo-Darwinism comes from the combination of two ideas. The acceptance that Darwin is right about all organisms on Earth having common ancestry and that evolution of life has occurred. But that Gregor Mendel is also right when he shows that inheritance factors are simply recombined, they don’t change through time.
I’m sorry, but while the first superficial description of common descent has at least a little merit, the second is complete twaddle. an utter strawman of the entire field of population and molecular genetics, let alone how genetics contributes to modern evolutionary theory.
uh, why exactly was Margulis given space here again, given that there appears to be no interest in Margulis actually addressing any of this drivel directly?
What a pleasure to write openly for Pharyngula even though, in principle, I am leery, even with this blog, of any internet participation.
leery, indeed; with good reason evidently – it’s pretty easy to call up some pretty disturbing statements, and an apparently vast ignorance of how the vast majority of evolutionary biologists view their own field:
Scientists too often know little about the cultural and historical context of their ideas. Neo-Darwinians biologists, for example, really believe that “evolution” is a subfield of biology, especially zoology. Hence they ignore the non-zoological components of evolutionary science (e.g., all of historical geology including especially paleontology; environmental science, ecology, atmospheric chemistry, microbiology, etc.)
*shakes head*
funny, even as an undergrad (let alone as a grad and post grad), all the evolutionary biologists I knew had an excellent grasp of the “non-zoological components of evolutionary science”, and often stressed their relevance even in courses on basic ecology.
“Several famous scientists, Frank Fenner, Frank Macfarlane Burnet, and Ian Clunies Ross famously injected themselves with myxoma virus, to prove it was not dangerous for humans. Why can’t HIV “rethinkers” do the same?”
Good question,I guess it’s probably due to the long incubation period?
I’m also kinda wondering how HIV denialists explain development of AIDS after occupational exposure or blood transfusion. And by wonder, I mean I wonder how high they jump to get through the hoops required to explain them away — is it as high as creationists’ leaps to explain away transitional fossils and pseudogenes?
As for self-injection, there’s been enough time since Duesberg started this contemptible crusade, for him to have developed AIDS, if he’d done the ‘experiment’ back when he started claiming AIDS wasn’t caused by HIV.
By the way, Tara has a post up about this on Aetiology.
I guess she decided she wasn’t going to let PZ have all the HIV deniers to himself. ;)
Yeah. Im a 23 year old kid who hasnt even started grad school yet, and Ive debunked some of her ‘science’ already on my blog.
Real impressive, that Culshaw.
PZ, You said on Tara’s re Lynn’s clarification of her HIV/AIDS beliefs:
“Unfortunately, the HIV denialist comments were all ignorant crap that only a deluded fool would find convincing. So that was a sigh of disappointment
Well, PZ,
Please give us your best explanation of the following points, so that we silly “deluded fools” and followers of Duesberg and Margulis may understand just why Lynn Margulis and Peter Duesberg are leading us foolish and deluded rethinkers astray.
What have you to say to the following:
1) Billions spent with zero cured,
2) Thousands gainfully employed with no intention of considering anything other than HIV,
3) More funding for HIV than other leading causes of death are given, even though other causes of death have a much higher percentage of overall mortality of the general population than HIV.
4)no known and proven or verified way, after 25 years of research, of knowing that HIV, if it exists as a contagiouus retrovirus, actually does anything damanging on a cellular level anywhere in the human body,
5) HIV is a retrovirus that grows in eternal t cell lines but is said to kill t cells in humans,
6) the longest term transmission study on sero opposite couples that showed exactly zero transmissions among sero opposites,
7) scientists, including discoverers Robert Gallo and Luc Montangnier, who all agree that unamed or unknown co-factors are necessary for disease progression but castrated Duesberg for saying it was the co-factors causing the disease,
8) Proven deadly and toxic treatments fastracked through the FDA with no long term study. AZT itself was approved after only 4 months of actual patient trials,
9) No hiv drugs are ever tested against placebo or against non treatment.
10) a virus so small that among viruses it is a miniature with barely the capability to infect a cell, yet is claimed to mysteriously be the cause of immune system depression.
11) a virus that is such a brilliant genius that it knows who is gay and who is straight, and
12) must obviously know who is black and who is white
as the virus is currently said to have infected 97 percent blacks and gays in the western world.
But most of all, PZ,
I was wondering if you could give us the reference for the following statement:
“HIV, the virus which causes AIDS”
I myself, as well as Lynn Margulis, Peter Duesberg, Karry Mullis, and all of the rest of the rethinkers would greatly appreciate some help with this, as none of us are able to find the reference.
Please do give us your own explanations for these confounding and puzzling questions, so that we denialists may return to your higher understanding of HIV ande AIDS, and be back in the good graces of civilization.
Well stated Lincoln! I wonder if you will get any ratiional answers to your questions. I would like to know why LDN is not being the drug of choice instead of toxic amti-virals. It certainly has a safe track record and has been proven to work. What more could one expect from a drug but of course big bucks. I bet that if it were an expensive drug and the patent had not ran out, it would be out there front and center. if the drug companies, the CDC and the NIH really cared about the patient’s health, they would be pushing this drug instead. Thank goodness there a some doctors out there with some common sense.
Lincoln,
I don’t have time or inclination to answer most of your points, many seem so obvious I’m surprised you can’t answer them yourself.
It is points like these that cause me to reject ‘rethinkers’ out of hand.
>11) a virus that is such a brilliant genius that it knows who is gay and who is straight, >and
>12) must obviously know who is black and who is white
If these two are a reason to reject the HIV/AIDS connection, than you’ll pretty much have to reject many, if not most, virus/disease connections since disease incidence is more often than not lopsided, wouldn’t you? Viral transmission is dependent on the opportunity for transmission of course: healthcare, population density, cultural practices and norms, travel, population insularity and many other factors will make one population more susceptible to viral infection than others. Seems quite straight-forward and easily understood.
But even given that, apparently the HIV isn’t such a genius since most people who have HIV or AIDS aren’t gay and a lot of white people have it too.
Well, here is another one I’ll answer because it won’t waste too much of my time. All one has to do to shoot this out of the water is know how to use google:
>9) No hiv drugs are ever tested against placebo or against non treatment.
Like these hiv drug tests that used control groups and placebos, found on the first page of a google search?
http://query.nytimes.com/gst/fullpage.html?sec=health&res=9D07E0DD1F3EF93BA15751C0A9619C8B63
http://www.nelm.nhs.uk/Record%20Viewing/viewRecord.aspx?id=577605
http://www.thebody.com/asp/may01/arca.html
http://www3.niaid.nih.gov/news/newsreleases/2000/il2-haart.htm
Give Tara’s blog (Aetiology) a browse, Trev. I don’t read it regularly, but even I recognized Lincoln straight away. You’ll see that portraying AIDS as targeting homosexuals and anyone with African ancestry seems a crucial point to Lincoln. I’m not sure why…I’ve gotten the impression that it has something to do with AIDS (whatever the cause) being a way to oppress gay black men, but that’s a guess. Tara or others would know better.
Copied from response on The Island of Doubt:
Ignoring the AIDS comment and focusing instead on Margulis’ comments regarding neo-Darwinism, I am surprised that you should accuse her of losing her skeptical edge. If anything, she is accusing you of losing your skeptical edge.
Specifically, she is simply restating Thomas Kuhn’s argument that science must hold certain truths as paradigmatic, and unquestionable, in order to function (ie – if you had to question whether calipers worked before you were allowed to use them, you would never make any progress). But what Margulis is accusing you of is holding so very, very dearly to neo-Darwinist thought that you are blinding yourself to possible new discoveries that could conflict, even if only the tiniest bit, with that paradigm (ie – you accept calipers as so totally incredible that you never find a better way of measuring things…say…quantum measurements). In other words, she is accusing you of the dogma and lack of skepticism that science supposedly avoids in order to make truly revolutionary discoveries. Holding on to paradigms allows you to make minor progress in your field – questioning them allows you to make revolutionary progress.
She’s telling you to start listening to arguments as arguments – on the weight of their points and evidence. Giving them their day in court.
Seems like a fairly reasonable, and utterly scientific, suggestion to me.
Poor Trev. Go back and re-read your links. All these studies involve background therapy (antivirals) for both groups. The placebos are randomly given in addition so that participants won’t know who got the test drug (blinded). It is considered unethical to have an untreated control group when testing new HIV drugs and the NIH doesn’t allow drug companies to do it.
What’s your explanation for the dramatic effect of anti-retroviral cocktails on HIV progression? Some of them (like the protease inhibitors” are pretty highly specific agents. Just by accident they happen to work?
Posted by: Steve LaBonne | March 12, 2007 11:00 AM
Dear Steve,
Non of the so-called “anti retroviral” drugs are specific to inhibiting or kiling “hiv”. The idea that “hiv” protease inhibitors are specific to “hiv” I am afraid are not true at all.
Many orthadox “aids” researches believe that the primary loss of “cd4” (be it that TH1/TH2 Balance, Eleni and the Perth Groupor Luc Montaignier or cominations of them all involving GSH and oxidation )the white cells claimed to be killed by “hiv” are lost through apoptosis, protease inhibitors just like antioxidants have been shown to inhibit reduce apoptosis induced by oxidizing GSH depleting drugs like AZT, hydrogen peroxide, radiation, morthine=heroine, they have also been shown to reduce “cd4” cell death/apoptosis INDEPENDANT of “viral-load”. They have been shown to start reducing apoptosis before the “viral-load” goes down and after “viral-load” increases “treatment failure=viral resistance”. They have also been shown to have a direct in vivo and in vitro effect on Kaposi sarcoma the “original” “aids” “SIGNAL” disease of “aids” that accounted for between 35% to 55% of the early cases of “aids” reported in the early 1980’s 97-100% of the Kaposi Sarcoma cases occured in gay bi men, not white heterosexuals, or heterosexual IV drug users just gay and Bi men. Nac o pro glutathione (GSH) drug has been shown in vivi and in vitro to reduce,inhibit and reverse KS, combo;s that contain P.I.’ increase intracellular GSH levels just like antioxidants like NAC doe and they may do so not through any effect on “hiv” or “cd4” but through increasing antioxidants specifical GSH and reducing oxidative effects. All anti “hiv” agents have BROAD SPECTRUM effects on all the “opportunistic-infections=O’I’s ” claimed to be caused by “low-cd4”. Many of the “syndromes=diseases-oppurtunisic-infections” occur in the absence of “low cd4” and on people on “sucessfull combination”
“hiv” do sometimes make many people better, they sometimes resolve and inhibit “O’I'”s and they can and do save and improve some lives.
But that does not prove that either “hiv” has been isolated or that “hiv” causes the diseses that CAN sometimes be called “aids”.
Please make sure that whenyou go to these links that after the end of the first post of this thread to click on “FIRST” otherwise you will not see and miss the many , many ,many studies that demonstrate the things others and I have stated about the NON SPECIFIC effects of “ARV’s” especially protease inhibitors.
thread titled.
ceramide,apoptosis,antioxidants,”cd4″,Atrophy,combo?
on health board of http://www.aidsmythexposed.com
http://groups.msn.com/AIDSMythExposed/healthissues.msnw?action=get_message&mview=0&ID_Message=15539&LastModified=4675613504475313222
Glutathione, NAC,selenium,antioxidants Th1/TH2 Balance “aids”
http://groups.msn.com/AIDSMythExposed/healthissues.msnw?action=get_message&mview=0&ID_Message=23579&LastModified=4675613879464003620
KS not Aids?
http://groups.msn.com/AIDSMythExposed/healthissues.msnw?action=get_message&mview=0&ID_Message=8565&LastModified=4675612127611304677
EGB-bilobalide”pcp”GSH-cell death
http://groups.msn.com/AIDSMythExposed/healthissues.msnw?action=get_message&mview=0&ID_Message=12189&LastModified=4675612286080019894
And of course the originators of the critical importance of GSH , oxidation /redox theory of “aids” and KS was the Eleni and the Perth Group http://www.theprethgroup.com , non others that the “real” discover of “hiv” prof luc montaignier has champoined, well researched and campaigned rightley for immediate (if some what late) use, research, developement, access, to pro GSH agents , antioxidants, food, clean water, vitamins, proteins, minerals.
Best wishes hugs
James
P.S this was written by John Kirkham , I helped John find some interesting papers . it was presnted by John in the BMJ deabete was allowed while Richard was there. In that banned , censored, debate news from the Editorial and a large study In the New England Journal of Medicine came out that a simple , primative, very cheap ($15 dollars a year) multi vitamin tablet reduced “aids” by 30%, reduced “viral-loads” by 30%, sustained “cd4”, rduced infections and could delay ,thus save money Billions and Billions,and toxicity which is amplyified in malnurished, oxidized people, prolong lives and improve lives and IF that person needs treatment some of these treatments can and I argue shuld be used ALONGSIDE the most important things GSH, oxidation, food, nutrician , antioxidants ,minerals especialy pro GSH like selenium . Where wasting millions of lives address these things now, forget the sideline story about if “hiv” does or does not exist, does “it?” singulary cause “aids” the important thing is to start demanding these agents are in place for every human effected by this blame it on “oxidizing hiv tat” or gp120 , is it multi – fractractial when combined with oxidizing agents like morphine-herione, cocaine, poppers. sperm in the rectcum from perhaps multiply donnors, poverty-malnutrician.
Who cares ? if ???? The important issue here start using these cheap , money saving, life saving, enhancing agents NOW with or without “arv’s”.
http://www.altheal.org/treatments/oxidative.htm
Some immune stimulating treatments and the scientific bases for them
John Kirkham and James Whitehead
http://www.altheal.org/treatments/oxidative.htm
If anything, she is accusing you of losing your skeptical edge.
idiot.
nobody is misunderstanding WHAT she is doing, rather only pointing out that her justifications and reasoning for doing so are based on not one, but several strawmen.
very much like the IDiots at the Disco institute do.
I suppose your one of those who thinks we should be “skeptical” of the moon landing, too eh?
oh, as to glutathionesurvival1:
Glutathione: New Supplement on the Block
Cure-All or Snake Oil?
*yawn* – the latest untested antioxidant overhyped snake oil.
you should change your handle so it’s at least slightly less obvious.
you people make me sick, and somehow I don’t think it’s a sickness that glutahione can “cure”.
Ichthyic,
No, I do not believe we should be skeptical of the moon landing, nor do I buy ID (as your StuDlYCaps would suggest), since I have yet to see decent evidence for either position. I also feel that the evidence Dr. Margulis offers above is flimsy, at best, but I follow it nonetheless, just in case the unexpected happens and it eventually exhibits its worth.
To that end, I do my best to listen to the evidence as presented and consider it on its merits, or lack thereof.
I try to keep in mind my own biases, or, if you prefer a less loaded term, “things which I take for granted,” lest they lead me astray. As an example, history tells me the sun will rise tomorrow, but if it didn’t, I wouldn’t scream “that’s impossible!” I would do the scientific thing and say “well, that was improbable. Obviously I thought something wrong, and now it’s time to find out why.”
I also generally try to avoid condescending knee jerk reactions or insulting my opponents with ad hominem remarks, as they tend to make me look incapable of carrying on a real debate, and they also tend to ossify my opponent’s position.
Why, you may ask? Because a reasonable adult debate would not be either otherwise. It would simply be two schoolchildren standing on either side of a fence screaming “YOU’RE the idiot,” “No, YOU’RE the idiot” at one another. It would be pointless. It would be worthless. It would be dogma.
In Reply to
#83A noted Mathematician (real science mind you) worked with HIV models for several years, but recently wrote her dismay that much of the science is pretty much bogus.
With all due respect but Culshaw is only a “noted” mathematician in “rethinker” circles. The reasons she gives in that opinion piece for her dismissal of HIV science are just regurgitations of factoids she has read in “rethinker” literature.
For instance she writes: The current testing protocol is to “verify” a positive ELISA with the “more specific” WB (which has actually been banned from diagnostic use in the UK because it is so unreliable).
The Western blot has not been banned in the UK. This is a myth that is only found in “rethinker” websites. Culshaw demonstrates that she gets her factoids from “rethinker” websites rather than the scientific literature. Culshaw makes it clear that it was not her own research that lead her to doubt that HIV causes AIDS but rather the “rethinker” literature.
Posted by: Chris Noble | March 13, 2007 08:54 PM ”
I have spoken several times in person and read Dr Philip Mortimors views on Western Blot being used as a “confirmatory” test for “hiv” antsbodies, western blots are NOT used in England and Wales since 1992, Dr Philip Mortimor is head of the virus reference division of Uk Public health Labority service PHLS. Western Blots are not used, please read medical literature written about western blots by Dr Phillip Mortimor. Those are the facts.
In Reply to
“#98oh, as to glutathionesurvival1:
Glutathione: New Supplement on the Block
Cure-All or Snake Oil?
*yawn* – the latest untested antioxidant overhyped snake oil.
you should change your handle so it’s at least slightly less obvious.
you people make me sick, and somehow I don’t think it’s a sickness that glutahione can “cure”.
”
I gave links to sever hundred scientific references your responce is childish, meaningless and has zero references.
Further more Glutathione is not new. Its existed ever since mankind has existed, its produced mainley in liver, NAC has been used in emergency medicine for over 40 years and is a precurser to glutathione.
Please learn basic biology and read some medical journalsor science journals. Please go to http://www.pubmed.com
put in the search bar glutathione hiv or glutathione aids, or glutathione kaposi sarcoma, or nac aids or nac hiv, or nac kaposi sarcoma, or nac or glutathione cancer or serach NAC , glutathione TB.
Science papers, studies, experiments are all that matters, bad manners, silly name calling and ignorance means nothing.
Please note that TB has always existed, TB has always caused wasting, TB has always caused immune suppression and TB has always been associated with poverty and malnutrician.
TB is can now define as “aids” with or without a “hiv” antibody test in Africa (courtesy WHO Bangai “aids” definition) and TB accounts for the majority of African “aids” cases, wasting can also be defined as “aids” and the microbacterium that causes TB can “cross-react” making a person with TB test “positive” for “hiv” antibodies.
http://www.aidsrestherapy.com/content/3/1/5
Glutathione and growth inhibition of Mycobacterium tuberculosis in healthy and HIV infected subjects
Vishwanath Venketaraman1 ,2 ,3 ,4 ,5 ,6 , Tatanisha Rodgers1 ,4 ,6 , Rafael Linares6 , Nancy Reilly1 ,4 ,6 , Shobha Swaminathan1 ,4 ,6 , David Hom2 ,6 , Ariel C Millman1 ,4 ,6 , Robert Wallis1 ,4 ,6 ,7 and Nancy D Connell1 ,2 ,3 ,4 ,5 ,6
1Division of Infectious Diseases, UMDNJ-New Jersey Medical School, Newark, NJ 07xxx xxxxxx, USA
2Center for Emerging and Re-emerging Pathogens, UMDNJ-New Jersey Medical School, Newark, NJ 07xxx xxxxxx, USA
3National Tuberculosis Center, UMDNJ-New Jersey Medical School, Newark, NJ 07xxx xxxxxx, USA
4Department of Medicine, UMDNJ-New Jersey Medical School, Newark, NJ 07xxx xxxxxx, USA
5Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, Newark, NJ 07xxx xxxxxx, USA
6New Jersey Medical School, UMDNJ-New Jersey Medical School, Newark, NJ 07xxx xxxxxx, USA
7PPD, 1213 N Street NW, Apt. A, Washington DC 20005, USA
AIDS Research and Therapy 2006, 3:5 doi:10.1186/1742-6405-3-5
The electronic version of this article is the complete one and can be found online at: http://www.aidsrestherapy.com/content/3/1/5
Received 29 December 2005
Accepted 20 February 2006
Published 20 February 2006
© 2006 Venketaraman et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
——————————————————————————–
Outline Abstract
Abstract
Introduction
Experimental methods
Results
Discussion
Acknowledgements
References
Intracellular levels of glutathione are depleted in patients with acquired immunodeficiency syndrome in whom the risk of tuberculosis, particularly disseminated disease is many times that of healthy individuals. In this study, we examined the role of glutathione in immunity against tuberculosis infection in samples derived from healthy and human immunodeficiency virus infected subjects. Our studies confirm that glutathione levels are reduced in peripheral blood mononuclear cells and in red blood cells isolated from human immunodeficiency virus-infected subjects (CD4>400/cumm). Furthermore, treatment of blood cultures from human immunodeficiency virus infected subjects with N-acetyl cysteine, a glutathione precursor, caused improved control of intracellular M. tuberculosis infection. N-acetyl cysteine treatment decreased the levels of IL-1, TNF-α, and IL-6, and increased the levels of IFN-γ in blood cultures derived from human immunodeficiency virus-infected subjects, promoting the host immune responses to contain M. tuberculosis infection successfully.
Tuberculosis (TB) is a major global health problem [7]. Approximately one-third of the world’s population is latently infected with Mycobacterium tuberculosis (LTBI). Individuals with LTBI have a 5-10% lifetime risk of developing active disease [7]. Human immunodeficiency virus (HIV) infected subjects with LTBI are at very high risk of developing active tuberculosis. Development of active TB in HIV patients is due not only to reactivation of latent M. tuberculosis infection but also due to increased susceptibility to primary progressive M. tuberculosis infection [7].
Innate and adaptive immune responses are required for successful control of M. tuberculosis infection. Macrophages provide first line defense against M. tuberculosis infection. Murine macrophages can be activated to kill intracellular M. tuberculosis by treatment with LPS (a stimulus for TNF-α expression, via triggering of toll-like receptors) and IFN-γ (a product of activated lymphocytes). Nitric oxide (NO) produced by infected macrophages is the main mediator (effector molecule) in this process. Like those of mice, human macrophages also acquire antimycobacterial activity through IFN-dependent interactions with lymphocytes [12]. However, exogenous IFN-γ does not enhance the mycobactericidal activity of isolated human macrophages as it does those of mice. Several studies indicate instead that direct cellular contact is required for the induction of antimycobacterial activity in human macrophages [6,33], and that this activity reflects caspase-mediated induction of apoptosis, triggering of toll-like receptors, the release of antibiotic peptides (e.g., granulysin), or unknown mechanisms [4,36].
Glutathione (GSH) is an antioxidant and plays a vital role in cellular detoxification and enhancement of immune functions [10]. Interestingly, HIV-infected people have subnormal GSH levels in their plasma, lung epithelial lining fluid, peripheral blood mononuclear cells (PBMC), and other blood cells [5,11,14,23]. It has been recently reported that the decreased GSH levels in PBMC of HIV-infected individuals is associated with a poorer prognosis [24]. Immunodeficiency due to HIV-1 represents the greatest recognized threat to successful containment of latent M. tuberculosis infection. The aim of this study was to examine the role of GSH in immunity against TB in samples derived from healthy and HIV infected subjects.
In our previous studies using macrophages from different sources, we have demonstrated that GSH plays a vital role in innate immunity against TB infection [40,41]. In our recent studies we have shown that GSH has static effect on H37Rv growth in vitro [41]. The mechanism of toxicity of GSH to mycobacteria is not yet known. One possibility is that the presence of high concentrations of GSH may result in an imbalance in a bacterial cell already containing an alternative thiol for regulating reduction/oxidation activity (e.g., mycothiol).
In the present study, we reexamined the extent to which GSH levels are decreased in HIV positive subjects. We also examined the relationship between GSH levels and the ability to kill intracellular M. tuberculosis, in association with other immune functions, such as cytokine production. GSH levels were modulated by treating blood samples with N-acetyl cysteine (NAC) to increase or buthionine sulphoximine (BSO) to decrease intracellular GSH pools. Our results suggest that the inability of immune cells from healthy and HIV subjects to contain TB growth may be a consequence of the inability of their macrophages to maintain adequate GSH levels during in vitro infection.
Subjects
A total of 20 subjects (10 healthy volunteer controls and 10 patients with HIV infection) were enrolled at UMDNJ-University Hospital of Newark and the NJ Medical School, in Newark, NJ. Subjects with HIV infection without tuberculosis (n = 10) were recruited at the Infectious Disease Clinic of UMDNJ-University Hospital. The Clinic is the site of several ongoing studies of HIV treatment; these studies provide anti-retroviral treatment (ART) to enrolled subjects without charge. Patient care was not altered by participation in this study. Patients were defined as being HIV-positive on the basis of a positive ELISA with a confirmatory Western Blot performed as part of their routine care in the clinic. The average CD4 numbers for HIV patients in this study was 423 ± 83/cumm. Only one patient had CD4 counts below 200/cumm. Seven patients were on ART and three patients were not on any treatment at the time of blood draw. Healthy subjects without HIV infection or a history of TB were recruited from the hospital and the university faculty and staff (n = 10). Healthy and HIV-positive subjects with a history of a positive tuberculin test (TST) were excluded from the study so as to maintain strict study definitions. This is according to the CDC recommendation that recognizes that a positive TST reflects latent TB infection.
Safety precautions for handling M. tuberculosis
All experiments with M. tuberculosis H37Rv were performed inside the bio safety level 3 (BSL-3) facility. The protocols for all experiments were approved by the UMDNJ Institutional Review Board, and the New Jersey Medical School Institutional Biosafety Committee. All experimental procedures were performed inside the biosafety cabinets in the BSL-3. All liquid and solid wastes from the experiments were treated with a disinfectant solution and then autoclaved.
Processing of H37Rv for infection
M. tuberculosis H37Rv was grown in 7H9 with albumin-dextrose complex (ADC). Static cultures of mycobacteria at peak logarithmic phase of growth (between 0.5 and 0.8 at A600) were used for infection. The bacterial suspension was washed and resuspended in RPMI containing AB serum. Bacterial clumps were disaggregated by vortexing five times with 3-mm sterile glass beads. The bacterial suspension was passed through a 5 μm filter to remove any further clumps. The total number of organisms in the suspension was determined by plating. Processed mycobacteria were frozen as stocks at -80°C. At the time of infection, frozen stocks of processed mycobacteria were thawed and used for macrophage infection.
Separation of monocytes from human blood
Human monocyte-derived macrophages (HMDM) were used to study the effects of IFN-γ and GSH in inducing intracellular killing of H37Rv. These experiments were performed only in blood samples from healthy subjects due to the non-availability of sufficient blood volume from HIV patients. Forty ml of blood from healthy subjects were used for monocyte isolation. PBMC were isolated by ficoll hypaque density centrifugation. PBMC were washed with PBS and resuspended in RPMI containing 5% AB serum. PBMC (10 × 106/ well) were distributed into Poly-DL-lysine coated 12 well plates and incubated overnight at 37°C, 5% CO2 in a humidified atmosphere, to allow monocytes to adhere to the plate. Non-adherent cells were removed by gentle washing and the adherent monocytes were cultured in RPMI containing 5% AB serum for 7 days before being used for infection experiments to allow differentiation to macrophages. The total number of macrophages per well (on day seven) was quantitated by detaching the macrophages from a single well by the addition of ice-cold accutase (Sigma). Viable detached macrophages were counted in a Neubauer counting chamber by trypan blue dye exclusion. The average number of macrophages per well on day 7 is approximately 5 × 105.
Macrophage infection
HMDM from healthy subjects were maintained in vitro as described above. Macrophages were infected with processed H37Rv at moi of 10:1. Macrophages were incubated with H37Rv for 2 h (for phagocytosis), after which extracellular organisms were removed by washing with PBS. Infected macrophages were maintained in RPMI containing 5% AB serum. Infected macrophage cultures were terminated at 4 h and 7 days after infection and treatment, to measure the intracellular viability of H37Rv. Cell free supernatants from infected macrophage cultures were diluted and plated for extracellular bacterial growth. Intracellular viability of H37Rv was determined by lysing the infected macrophages with sterile distilled water and plating the lysate on 7H11 enriched with ADC, to enumerate mycobacterial colonies.
Survival of H37Rv in IFN-γ, LPS treated HMDM
IFN-γ is considered a predominant activator of microbicidal functions in macrophages and is essential for prevention of uncontrolled progression of M. tuberculosis infection [2,18,27]. We therefore studied the survival of H37Rv in IFN-γ, LPS treated HMDM. HMDM were maintained in vitro and infected with H37Rv, as described previously. H37Rv-infected HMDM were treated with IFN-γ (100 U/ml) and LPS (1 μg/ml), the cultures were terminated at 4 h and 7 days after infection and treatment, to determine the intracellular viability of H37Rv inside unstimulated and IFN-γ, LPS-stimulated macrophages.
Survival of H37Rv inside NAC treated HMDM
We determined the effects of GSH in human macrophage mediated growth inhibition of intracellular H37Rv. HMDM were treated with different concentrations of NAC. Cysteine uptake is considered as rate-limiting step for synthesis of GSH. The most efficient way to increase the levels of cysteine in cells grown in vitro is to supply the culture medium with NAC. NAC is easily taken up by the cells and is non-toxic. Intracellularly, NAC is de-acetylated and cysteine is utilized for GSH synthesis. H37Rv infected HMDM were treated with 5, 10, 15, and 20 mM NAC, and intracellular growth of H37Rv was studied. Infected macrophage cultures were terminated at 4 h and 7 days, after infection and treatment. Infected macrophages were lysed and plated for mycobacterial colonies.
Whole blood mycobactericidal assay
Mycobacteria added to heparinized blood (after dilution with tissue culture medium), are rapidly ingested by monocytes and other phagocytic cells such as neutrophils. This model differs from other intracellular infection models in that all blood elements are represented. Interactions of infected monocytes with natural killer cells and antigen-specific T cells result in control of intracellular growth. In contrast to the studies with isolated macrophages, the whole blood assay requires a low volume of blood. Blood was diluted at the following proportion: 300 μl of blood from healthy subjects and patients were diluted to 1 ml with RPMI. Blood cultures were infected with 105 CFU of H37Rv. GSH levels in blood cultures were altered using agents such as NAC (10 mM) and BSO (500 μM) that specifically increase and decrease intracellular GSH. The effect of altered GSH levels on M. tuberculosis survival was studied. Treatment of cells with BSO causes inhibition of GSH synthesis. BSO specifically inhibits the activity of γ-glutamyl-cysteinyl synthetase enzyme, that catalyses the first step reaction in the synthesis of GSH. Blood cultures were treated with either NAC or combination of NAC and BSO for 24 h prior to infection. H37Rv infected whole blood cultures were incubated at 37°C and harvested at selected intervals (2 h and, 48 h) by sedimentation at 2000 rpm for 10 min. Supernatants were used to determine cytokine levels and extracellular mycobacterial growth. Host cells were disrupted by addition of sterile water. The lysates were plated on 7H11 medium enriched with ADC for mycobacterial colonies.
Assay of GSH
Intracellular GSH levels in PBMC, red blood cells (RBC), and plasma, from healthy individuals and HIV positive subjects were assayed by spectrophotometry, using a GSH assay kit procured from Calbiochem. This approach is used to determine whether GSH levels are decreased in all blood components or just in some specific components. Plasma and cell lysates of RBC and PBMC, derived from healthy and HIV positive subjects, were mixed with equal volume of ice cold 5% metaphosphoric acid (MPA) and centrifuged at 3000 rpm for 15 minutes. Supernatants were used for GSH assay, as per the manufacturer’s instruction. Plasma, RBC, and PBMC were separated from whole blood by density gradient centrifugation using ficoll hypaque. Samples were also used for protein assay by Bradford’s method using Bio Rad reagent.
Cytokine assay
Blood cultures were prepared by afore mentioned methods. Blood cultures from healthy subjects and HIV patients were treated as follows: no treatment, infection with H37Rv, and infection with H37Rv and treatment with NAC. Cultures were terminated at 2 h and 48 h, after infection. Uninfected cultures were terminated at the same time points. Cultures were centrifuged at 2000 rpm for 10 min. Cell free supernatants from healthy and HIV patients were used for the cytokine assay, which was performed using a Beadlyte kit procured from Upstate. This is a highly sensitive kit that can be used to detect multiple cytokines in tissue culture samples. A monoclonal antibody specific for a cytokine is covalently linked to a fluorescent bead set, which captures the cytokine. A complementary biotinylated monoclonal cytokine antibody then completes the immunological sandwich and the reaction is detected with streptavidin-phycoerythrin using a Luminex. The assay was performed as per the manufacturer’s protocol.
Statistical analysis
Statistical analysis of the data was carried out using Statview program and the statistical significance was determined using unpaired t test. Data from cytokine assays was analyzed by non-parametric test (Kruskal-wallis). Differences were considered significant at a level of p < 0.05. Figures Figure 1 Growth of H37Rv in unstimulated (Fig 1a), IFN-γ, LPS (Fig 1a), and NAC treated HMDM (Fig 1b) Figure 2 Spectrophotometric assay of GSH in PBMC (Fig 2a) and RBC (Fig 2b), derived from healthy and HIV positive subjects Figure 3 Growth of H37Rv in whole blood cultures of HIV patients Figure 4 IL-1, TNF-α, IL-6 and IFN-γ assays in blood culture supernatants Figure 5 IL-10 assay in blood culture supernatants Figure 6 Model describing direct and indirect effects of GSH in growth control of H37Rv in blood cultures derived from healthy and HIV-infected subjects Survival of H37Rv in HMDM We studied the survival of H37Rv in HMDM from healthy subjects. H37Rv-infected HMDM were treated with IFN-γ (100 U/ml) and LPS (1 μg/ml), and the intracellular viability of H37Rv inside unstimulated and IFN-γ, LPS-stimulated macrophages was compared. Figure 1a shows results from six different subjects performed in triplicate. We observed significant growth of H37Rv inside unstimulated HMDM between 1 h and 7 days (Fig 1a). The increase was almost four fold. Stimulation of HMDM cells with IFN-γ, LPS also resulted in significant growth of intracellular H37Rv (Fig 1a). However, the increase in H37Rv growth was less than three-fold (Fig 1a). To examine whether GSH plays a major role in human macrophage killing of H37Rv, HMDM from healthy volunteers were treated with 5, 10, 15, and 20 mM NAC, and intracellular growth of H37Rv was measured. Experiments performed in six different subjects show that treatment of HMDM with 10 mM NAC resulted in stasis in H37Rv growth in three out of six subjects (Fig 1b). Treatment of HMDM with NAC at 5 mM and 15 mM induced growth inhibition of H37Rv, in one out of six, and two out of six subjects, respectively (data not shown). Treatment with 20 mM NAC had no effect on growth inhibition of H37Rv (data not shown). Therefore, NAC at 10 mM is more effective in inducing growth control of M. tuberculosis as compared to IFN-γ, LPS, or other concentrations of NAC (Fig 1b) in isolated HMDM. Whole blood model Several studies indicate that direct cell contact is required for induction of antimycobacterial activity in human macrophages [6,33], and that this activity reflects caspase-mediated induction of apoptosis, triggering of toll-like receptors, the release of antibiotic peptides (e.g., granulysin), or unknown mechanisms [4,36]. Mycobacteria are rapidly ingested by phagocytic cells when added to heparinized blood (after dilution with tissue culture medium). This model differs from other intracellular infection models in that all blood elements are represented. We therefore tested whether interaction of monocytes with other immune cells will lead to growth inhibition of intracellular H37Rv using whole blood cultures, which provides a micro-environment that is conducive for cellular interactions. Whole blood mycobactericidal assay in healthy subjects Blood from healthy volunteers was diluted as described and treated with none or 10 mM NAC. The blood cultures were then infected with 5 × 105 CFU of processed H37Rv. Infected blood cultures were terminated at 2 h and 48 h after infection to determine the intracellular viability of H37Rv. Cell suspensions were centrifuged to separate the cell free supernatants and pellets. Supernatants were diluted and plated for extracellular bacterial growth. Intracellular viability of H37Rv was determined by plating the diluted blood cell lysates on 7H11. Infection of blood cultures with H37Rv resulted in almost two-fold increases in the intracellular growth of H37Rv (Fig 1c). The increase in H37Rv growth was statistically significant. Treatment of blood cultures with NAC (10 mM), caused growth inhibition of H37Rv in all seven individuals tested (Fig 1c). The data in Fig 1c are averages from seven healthy subjects. Treatment of cultures with BSO abrogated the growth inhibition effect of NAC (Fig 1c). These results indicate that growth inhibition of H37Rv in NAC treated blood cultures is due to combination of direct antimycobacterial effects of GSH and activation of immune cells induced by GSH. Levels of GSH in blood samples from healthy and HIV-positive subjects Intracellular GSH levels in PBMC and RBC were assayed by spectrophotometry as described. We observed a significant and more than 50% decrease in intracellular GSH levels in PBMC (Fig 2a) and RBC (Fig 2b) from HIV patients compared to healthy subjects. Data shown in Fig 2 are averages from six healthy and six HIV-infected subjects. We observed no difference in the plasma GSH levels between healthy and HIV patients. Growth control of H37Rv by NAC-treated blood cultures from HIV patients Intracellular growth of H37Rv was monitored in blood cultures of HIV-positive subjects. We observed a significant growth of H37Rv in unstimulated blood cultures (Fig 3a). NAC treatment induced growth inhibition of intracellular of H37Rv. Data in Fig 3b are averages from data obtained from eight different HIV-positive subjects. BSO treatment abrogated the inhibitory effect brought about by NAC treatment (Fig 3c). Assay of cytokines in blood culture supernatants from healthy and HIV-positive subjects Cytokines were measured in blood culture supernatants from healthy and HIV-infected subjects. Interestingly, in HIV subjects, H37Rv infection induced the blood cultures to produce increased levels of pro-inflammatory cytokines such as IL-1, TNF-α, and IL-6 (Fig 4a, 4b, 4c). H37Rv infection induced almost three fold increases in IL-1 production, compared to uninfected controls (Fig 4a). NAC treatment of H37Rv infected cultures down-regulated IL-1 levels (Fig 4a). Compared to uninfected controls, H37Rv infection induced seven fold increases in TNF-α levels in two patients tested (Fig 4b). NAC treatment of H37Rv infected cultures caused reduction in TNF-α levels (Fig 4b). H37Rv infection induced almost ten fold increases in IL-6 production, in three patients tested (Fig 4c). NAC treatment reduced the levels of IL-6 to those found in the uninfected control. We also observed that infection of HIV blood cultures with H37Rv caused six fold increases in IFN-γ production in two patients and three fold increases in one patient (Fig 4d). In comparison to untreated controls, NAC treatment of H37Rv infected cultures induced ten fold increases in IFN-γ production in two patients and almost four fold increases in one patient (Fig 4d). In summary, our studies show that NAC treatment down-regulated the synthesis of IL-1, IL-6, and TNF-α and increased the levels of IFN-γ (Fig 4a, 4b, 4c, 4d). With the exception of IL-10, all other cytokines produced by healthy subjects showed no clear trend. The regulation of IL-10 synthesis in response to H37Rv infection and NAC treatment was similar in healthy subjects and HIV patients. H37Rv induced almost ten-fold increases in IL-10 levels in both healthy and HIV-infected subjects (Fig 5a, 5b). Furthermore, NAC treatment reduced the levels of IL-10 to those found in uninfected controls, in both healthy subjects and HIV patients (Fig 5a, 5b). Development of TB in HIV infected patients is based on a predisposition to reactivation of latent M. tuberculosis infection and to susceptibility to primary progressive M. tuberculosis infection [9]. However, the relationship of host immune responses to the development of TB during different stages of HIV disease is not clear. The opportunistic behavior of M. tuberculosis during human HIV infection can be explained by suppression of type-1 responses at the level of antigen-presenting cells, CD4 T cells and effector macrophages. In vitro studies have shown that lowering of intracellular GSH levels decreases cell survival, alters T cell functions and increases HIV replication, NF-kB activation, and sensitivity to TNF-α induced cell death [10,11,19]. A role has also been proposed for GSH as a carrier molecule for NO. Nitric oxide also reacts with GSH to form GSNO, an NO donor with greater stability [34,35]. We first reported that GSH facilitates the control of intracellular M. bovis BCG in NO-deficient macrophages derived from iNOS knock out mice, and in HMDM [40]. These studies indicated that GSH has direct antimycobacterial activity distinct from its role as an NO carrier. Furthermore, in our recent studies we demonstrated that GSH is vital for growth control of intracellular H37Rv in J744.1 macrophages [41]. It has been reported that production of IFN-γ is crucial to the control of M. tuberculosis infection [18]. Impaired production of IFN-γ correlates with progression of immunodeficiency and is likely related to abnormalities in the IL-12-IFN-γ axis [8,31]. We therefore tested the growth of H37Rv in HMDM from healthy subjects that are unstimulated or stimulated in vitro with IFN-γ, LPS. We observed a significant, four-fold increase in growth of H37Rv inside unstimulated HMDM, between 1 h and 7 days (Fig 1a). Stimulation of H37Rv-infected HMDM cells with IFN-γ, LPS also resulted in a three-fold increase in growth of intracellular H37Rv (Fig 1a). Since our earlier studies suggested a role for GSH in innate immunity against M. tuberculosis, we tested whether NAC treatment would induce HMDM to inhibit the growth of H37Rv. We observed that NAC at 10 mM concentration induced growth inhibition of H37Rv in three out of six healthy individuals tested (Fig 1b). Although normal levels of GSH are present in cells derived from healthy subjects, those levels might decrease during oxidative and nitrosative stress generated during TB infection. Therefore, addition of NAC to HMDM caused growth inhibition of M. tuberculosis by augmenting intracellular GSH levels. These results suggest that growth inhibition of H37Rv in NAC treated HMDM is due to the direct antimycobacterial effects of GSH. Furthermore, the inability of HMDM from some healthy individuals to inhibit M. tuberculosis growth is probably due to the inability of macrophages to maintain adequate GSH levels, despite NAC treatment. Reply Recommend Message 30 of 35 in Discussion From: GlutathioneSurvival1 Sent: 7/9/2006 3:05 PM Part two of two. As described before, innate and adaptive immunity are essential for successful elimination of M. tuberculosis. Macrophages interact with other immune cells in vivo, for successful growth retardation of M. tuberculosis. The whole blood model of infection resembles an in vivo system in promoting cellular interactions. This model differs from other intracellular infection models in that all blood elements are represented. Infection of blood cultures from healthy volunteers with H37Rv resulted in an almost two-fold increase in H37Rv growth (Fig 1c). The increase in H37Rv growth was statistically significant. In contrast to HMDM, treatment of blood cultures with NAC (10 mM) caused growth inhibition of H37Rv, in all seven individuals tested (Fig 1c). Our results suggest that growth inhibition of H37Rv in NAC treated blood cultures is due to direct antimycobacterial effects of GSH and due to activation of blood cells induced by GSH. We have confirmed the work of others that GSH levels are decreased in patients with HIV-1 infection [5,11,14,23], and then hypothesized that this decrease would be associated with reduced capacity of monocytes to kill intracellular M. tuberculosis. We further proposed that NAC treatment would improve the killing of M. tuberculosis. We tested our hypothesis by determining GSH levels in healthy and HIV positive subjects. We observed a significant and more than 50% decrease in GSH levels in PBMC and RBC from HIV patients compared to healthy subjects (Fig 2a, 2b). Since GSH enhances innate and adaptive immune functions, GSH deficiency in PBMC may contribute to the progressive immune dysfunction of HIV infection. Macrophages play a central role in HIV and TB infection because they are among the first cells to be infected [19]. Moreover, macrophages serve as an important reservoir for both HIV and M. tuberculosis. The major obstacle to eradication of HIV is latent virus in these reservoirs which has prompted the search for new drugs and strategies to protect this cell compartment. Erythrocytes have been used as a carrier system to deliver antiretroviral molecules to macrophages selectively. Fraternale et al [19] have reported that treatment of mice with AZT+DD1+GSH-loaded RBC significantly reduces the proviral DNA content, compared to mice treated with AZT+DD1. This result is consistent with our hypothesis and suggests that low levels of GSH in RBC, as observed in this and other studies, will affect the GSH carrier functions of RBC, compromising GSH delivery to macrophages. In order to determine the effects of NAC treatment on PBMC and RBC in reducing the growth of intracellular H37Rv, whole blood cultures from HIV patients were treated in vitro with NAC and infected with H37Rv. We observed significant growth of H37Rv in unstimulated blood cultures from HIV patients (Fig 3a). In vitro NAC treatment to blood cultures derived from HIV subjects caused inhibition in growth of intracellular H37Rv (Fig 3b). Furthermore, BSO treatment abrogated the inhibitory effect brought about by NAC treatment (Fig 3c). This suggests that restoration of GSH levels in HIV subjects caused enhancement in immune cell functions to contain M. tuberculosis growth. The decreased GSH content in immune cells of HIV-positive individuals was atleast in part attributed to the decreased in plasma cysteine and increased plasma glutamate (an inhibitor of cysteine permeation via the Xc- transport system), as observed during early infection. The decreased intracellular GSH and plasma cysteine observed in HIV patients is due to chronic oxidative stress, which may lead to the progression of the disease. The decreased availability of cysteine can be overcome to some extent by the cysteine precursor NAC [13]. A recent report of a carefully conducted clinical trial indicates that NAC treatment improves the clinical situation and delays the HIV disease progression [24]. This study showed that long-term administration of NAC to AIDS patients improves their hematological profile, GSH content and life expectancy [24]. We measured cytokine levels in whole blood culture supernatants from healthy and HIV infected subjects. No clear trend in cytokine profile was observed in healthy subjects. Interestingly, we observed that in vitro infection with H37Rv induced the whole blood cultures from HIV patients to synthesize increased levels of cytokines such as IL-1, TNF-α, IL-6 and IL-10 (Fig 4, 5). IL-1, TNF-α, IL-6 are the early pro-inflammatory cytokines produced by monocytes after various bacterial infections and share a wide array of biological activities [4,5]. In vitro studies have shown that mycobacterial preparations, including lipoarabinomannan, can cause the release of TNF-α and IL-1 from human PBMC [25,42,44]. The release of pro-inflammatory cytokines after mycobacterial infection is a host immune response that may be propitious or deleterious to the host. Newman et al. reported that increased survival of M. avium intracellulare (MAI) in isolated macrophages is correlated with the efficiency with which TNF-α and IL-6 are produced in response to MAI infection [28]. Nevertheless, increased levels of these pro-inflammatory cytokines may be disadvantageous to the host because they not only cause acute-phase events, such as fever, but also mediate cachexia, hemorrhagic necrosis and lethal shock [29,30,37]. TNF-α by classical cascade is known to up-regulate the levels of IL-1 and IL-6. Elevated levels of IL-6 are present in plasma of patients with TB [15]. Studies by Van Heyningen et al [39] indicate that macrophages infected with M. bovis BCG released copious amounts of IL-6 which in turn inhibited the macrophage capacity to induce proliferation of CD4 T cell hybridoma. Nagabhushanam et al. [26] reported a novel function of IL-6 in inhibiting cellular immune response to eradicate M. tuberculosis infection. Their studies show that IL-6 produced by M. tuberculosis-infected macrophages selectively inhibited macrophage responses to IFN-γ. In other words, secretion of IL-6 by M. tuberculosis-infected macrophages may contribute to the inability of IFN-γ to eradicate M. tuberculosis infection [26]. The high levels of IL-6 released by infected macrophages have implications for co-infection with HIV [32]. Mycobacterial infections are one of the most common AIDS-defining illnesses and may even accelerate progression to AIDS [17]. The two infections seem to synergize, causing a shift of the host-pathogen balance in favor of the pathogen, which cannot be reversed by treatment with antimycobacterial agents [43]. TNF-α and IL-6, as well as IL-1, can increase HIV replication [3,21]. Thus, decreasing the pro-inflammatory cytokine production in vivo may enhance the control of viral replication. Elevated levels of IL-6, TNF-α and IL-10 have been described previously in cases of advanced HIV disease [1,20,22]. Therefore, increases in the levels of pro-inflammatory cytokines will cause a positive feedback loop in which the two infections complement one another, leading to accelerated progression of both diseases. In our studies, we observed that NAC treatment caused down-regulation of the synthesis of IL-1, IL-6, and TNF-α (Fig 4a, 4b, 4c), and up-regulation of the synthesis of IFN-γ (Fig 4d). These results suggest that GSH might have a crucial role in vivo in reducing the levels of pro-inflammatory cytokines thereby protecting the host against disease progression. Active TB is associated with suppression of T cell responses [17] and enhanced production and activity of immunosuppressive such as IL-10. IL-10 has been shown to be produced by macrophages infected with mycobacteria. IL-10 and TGF-β overlap with each other in many of their biological effects including, inhibition of T cell proliferation and IFN-γ production [21]. Elevated levels of IL-10 in serum during advanced HIV infection may enhance immune suppression, allowing opportunistic infections [21]. In our studies, we observed that NAC treatment decreased the levels of IL-10 favoring immune activation (Fig 5b). We demonstrate growth inhibition of intracellular H37Rv in our in vitro studies using NAC-treated blood cultures from HIV patients. Furthermore, treatment of blood cultures with NAC modulated the production of cytokines in favor of the host. As described in the model (Fig 6a), our results strongly indicate that the immune cell enhancing and antimycobacterial functions of GSH are important for growth control of H37Rv in blood cultures from healthy and HIV-infected subjects (Fig 6a). Additionally, NAC treatment down-regulated the synthesis of IL-10 and pro-inflammatory cytokines in blood cultures from HIV-infected subjects favoring immune activation (Fig 6b). Current interventions to prevent tuberculosis in areas where TB and HIV are endemic, such as sub-Saharan Africa, have serious limitations. ART is limited by its cost and by its requirement for a sophisticated health care delivery system. Isoniazid chemoprophylaxis has limited efficacy in regions of high TB transmission, particularly in highly susceptible individuals with advanced HIV infection. In addition, isoniazid is ineffective against INH-resistant TB strains, which may account for 10-20% of all cases in some areas. NAC is inexpensive and non-toxic (it is considered a food supplement in the US, and is available without prescription in health food stores). The findings from this study may lead to long-term research that will be of potential importance for control of TB worldwide. Acknowledgements This work is supported by UMDNJ Foundation Grant (V.V), and American Heart Association-Scientist Development Grant 0335370T (V.V). 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This link has to do with the problems with ELISA and WB testing in it’s usage in testing for Lyme Disease-I think there are some good links that beg the question: If these test don’t work well for one thing, then how well do they work for somthing else? Science makes mistakes-so do doctors…look at Vioxx. In life we must always ask questions-we must always look at both sides and research.
Link: http://www.centuryinter.net/tjs11/bug/blot1.htm
The level of childishness and intellectual dishonesty displayed on this thread by defenders of the HIV hypothesis in mind boggling. They site no studies to back up their position and call others names as if they never matured past adolescence.
It is impossible to have a scientific debate if one side refuses to actually live up to the terms of rational debate. But maybe there is a reason in this – namely they have nothing to back up their position, except a legacy of death by prescription.
holy crap.
glutathione boy should be banned for excessive use of cut and pasting entire articles *ala Drew* AND commercial spamming.
yikes.
Chris Noble said that Dr. Robert Wilner “jabbed” himself, not injected himself with HIV. I accessed a couple of google searchs done by others.
One on the wording “inject”
http://www.google.com/search?hl=en&q=wilner+%22injected+himself%22+HIV&btnG=Search
Another on the wording “Jabbed”
http://www.google.com/search?hl=en&q=wilner+jabbed+HIV+needle&btnG=Search
May well be word games.
Ichthyic
“holy crap.
glutathione boy should be banned for excessive use of cut and pasting entire articles *ala Drew* AND commercial spamming.
yikes.”
I partly agree it is in bad taste to reprint entire,lengthy articles when a simple quote and link will do.
Hey Glutheboy,
For a better, more sophisticated response:
1. Sum up your point in one or two concise sentences.
2. Provide LINKS to your references.
Brevity is best. Long posts lose people. Stick to the science to make your point, leave out personal attacks or responses to personal attacks. Increase your effectiveness on blogs.
Chris Noble said in post number 63:
“Raphael’s sister has described how he succumbed to Kaposi’s sarcoma, MAC, systemic candiasis and PCP before finally dying. These are all rare opportunistic diseases that are classic manifestations of HIV/AIDS.”
In regard to KS Gallo has said:
“”In 1994, (HIV co-discoverer) Robert Gallo quietly admitted that Kaposi’s Sarcoma (KS) — the major AIDS defining illness in gay men — could not be caused by HIV. But this was never reported in the mainstream press. Gallo told the audience of scientists and activists at the ’94 NIDA meeting that HIV couldn’t cause KS and that he’d never even found it in T-cells, which HIV is supposed to kill. He said, ‘I don’t know if I made this point clear, but I think that everybody here knows — we never found HIV DNA in the tumor cells of KS. And, in fact, we’ve never found HIV DNA in T-cells. So in other words, we’ve never seen the role of HIV as transforming [cancer-causing] in any way.'”- Quote from Boston Dig, 2003.
Gallo now says HHV-8 is part of KS-this can be found just by using Google. One can have HHV-8 without HIV. There is also a connection between Poppers and KS that others have written about-even the Orthodox.
See, even Gallo has shifted the 1984 paradigm a half an inch-at least.
Thank you Ms. Margulis for asking questions. You have nothing to gain from this view point in terms of money or press-you are fighting more against a kind if Religion than a science-and that takes a great amount of courage.
Poor Wayne,
The comment said:
>9) No hiv drugs are ever tested against placebo or against non treatment.
Those links proved these drugs WERE tested against placebos AND against non-treatment of the drug being tested.
To expect a dying patient (with cancer, HIV, or whatever other disease) to be left completely untreated while testing a different treatment and then say that is proof of malfeasence or bad science is just plain ignorant, ludicrious or disingenious.
That is what that question on this absurd list is doing.
Trev,
Most HIV+ patients in the US are asymptomatic and it would not be difficult to identify a control group of untreated patients. Unfortunately, almost all clinical trials are with 2 or 3 groups – all treated with HAART. For example combivir/viramune against Atripla. Atripla is not tested against an untreated group. There are many patients with T-cells between 200 and 350 and even 500 who are not sick and who aren’t on HAART who could be a control group.
J,
Gallo and others knew a long time before 1994 that HIV was not the direct cause of KS. It was proposed fairly early that KS was caused by another sexually transmitted microbe by Valerie beral and others.
HHV-8 was subsequently discovered and its role in the pathogenesis of KS is firmly established with epidemoiolgy and animal models to support it.
HIV is believed to increase the risk of getting KS by a) immune suppression and b) HIV-tat activation of HHV-8.
Even Harry Haverkos, the champion of the poppers theory accepts the evidence for HHV-8 and HIV in KS.
While KS, MAC, systemic candidiasis and PCP all occur in the absence of HIV they are indications of profound immune suppression and AIDS. Do you want me to believe that Raphael Lombardo getting these opportunistic infections after being infected with HIV for a number of years was just a massive coincidence?
You can deny the connection between HIV and AIDS until the cows come home but it won’t change the fact that Rapahael Lombardo died from AIDS after Duesberg told him he didn’t have to worry about being infected with HIV.
I have spoken several times in person and read Dr Philip Mortimors views on Western Blot being used as a “confirmatory” test for “hiv” antsbodies, western blots are NOT used in England and Wales since 1992, Dr Philip Mortimor is head of the virus reference division of Uk Public health Labority service PHLS. Western Blots are not used, please read medical literature written about western blots by Dr Phillip Mortimor. Those are the facts.
I have read the literature. Towards error-free HIV diagnosis: guidelines on laboratory practice.
The Western blot has not been banned in the UK. It is still used by many labs including the Virus Reference Department.
What the article does say is “In many countries laboratories employ a two-test algorithm that examines repeatedly EIA screen reactive specimens by Western blot, but in England and Wales the prevailing approach has been, and remains, to employ at least two different tests following the initial reactive screening test, as recommended by the World Health organisation.”
This is a far cry from the claim that the Western blot has been banned because it is completely unreliable.
“I partly agree it is in bad taste to reprint entire,lengthy articles when a simple quote and link will do.”
I already did this DAYS ago, and no one has yet to even acknowledge visiting the link, let alone (gasp!, I know v troublesome to “inform oneself”) read the scientific papers:
http://www.reviewingaids.org/awiki/index.php/Template:Documents
“The following is a list of the most damaging documents available in the scientific literature, which refute the HIV/AIDS hypothesis, rebut orthodox “evidence” of HIV causation, reveal the fraudulent nature of the HIV tests, and expose the sociological motivations and political maneuverings behind the HIV paradigm.”
There is enough at this link to hold your attention for a fortnight, but you have to read it first. The raw scientific literature itself, an amazing tool — if you choose to use it.
BTW, to the person who listed all those remarkable studies on “HIV drugs”, most of those if I remember used CD4 counts or viral load as surrogate markers. Do you remember reading the quotes I posted above earlier?? Even the orthodoxy admits now that CD4 counts and viral load numbers are practically WORTHLESS.
I was expecting (hoping) maybe the quality of blog poster here would be slightly better than…other well-known blogs at this site to encounter this issue (no names, of course…)
Guess my hope was in vain…
Let’s face it, no one who is not a dissident is going to read links to an HIV dissident site, especially when some of the papers are by Duesberg. People may read papers from mainstream scientists so long as they support their own arguments. Everyone here is interested in furthering their own arguments. Period.
Chris Noble: Why is a positive Elisa test confirmed by two additional Elisa tests in England and Wales? And if that second test is negative and the third positive, do they just keep testing until they have a majority? If the Elisa test is 99% accurate as advertised, why do they continue testing if positive?
It seems a confirmatory test should be different than the initial.
Let’s face it, no one who is not a dissident is going to read links to an HIV dissident site, especially when some of the papers are by Duesberg. People may read papers from mainstream scientists so long as they support their own arguments. Everyone here is interested in furthering their own arguments. Period.
I am not a “dissident” and I have read all of Duesberg’s articles.
Contrary to the normal assertion of “rethinkers” I have come to my conclusions based on reading all the evidence.
Not only have I read Duesberg’s articles but I have checked his claims with the “orthodox” literature. It is only after this that I concluded that duesberg is full of crap.
Chris Noble: Why is a positive Elisa test confirmed by two additional Elisa tests in England and Wales? And if that second test is negative and the third positive, do they just keep testing until they have a majority? If the Elisa test is 99% accurate as advertised, why do they continue testing if positive?
It seems a confirmatory test should be different than the initial.
I posted a link too: Towards error-free HIV diagnosis: guidelines on laboratory practice. If you are interested in the protocols that are used for diagnosing HIV infection then it would be a good idea to read this article rather than the nonsense you find on “rethinker” websites.
The same ELISA test is not simply repeated. Different test kits with a different set of antigens (viral lysate/recombinant protein/synthetic peptides) and/or a different construction are used. It is highly unlikely that a sample will give a false reactive reading on a number of different tests.
It should be obvious that a single test with a testki with a specificity of 99% is not adequate for diagnosis. If 1000 people were tested this would result in 10 false positives. This is why protocols involving several different tests are used.
My reply to Mr Christopher Nobels comments on Kaposi Sarcoma “HHV-8 was subsequently discovered and its role in the pathogenesis of KS is firmly established with epidemoiolgy and animal models to support it. ”
can be found here
http://groups.msn.com/AIDSMythExposed/general.msnw?action=get_message&mview=0&ID_Message=27986&LastModified=4675614897007893766
Please note there are 3 animal models of inducing KS “like” legions and 2 of them didnt contain “hhv-8”.
And the epidemology does not support “hhv-8” causing KS in people with “hiv” or “aids”. References at the above link and the link I left about KS not “aids” earlier.
Thanks for the link Chris, but I don’t understand why England and Wales wouldn’t use the Western blot, as Dr. Harold Oster on iVillage says its chance of a false positive are less than 1 in 250,000, while John Hopkins says on its website 2% of the Elisa tests it gives are false positives. Elisa’s may be cheaper, but for such an important test everyone should use WBs.
I think you are having such problems because Peter Duesberg’s arguments are compelling. So are the Perth Group’s. As they are both discredited by mainstream scientist I see no advantage for them other than their conviction. Seems as if they would have it easier to go along with you. I think it is also that a quarter century has passed and not much progress has been made. HIV is Superman!
In reply to Mr Christopher Nobels comments on “hiv” Western Blot antibody tests in England and Wales.
The Western blot has not been banned in the UK. It is still used by many labs including the Virus Reference Department.
What the article does say is “In many countries laboratories employ a two-test algorithm that examines repeatedly EIA screen reactive specimens by Western blot, but in England and Wales the prevailing approach has been, and remains, to employ at least two different tests following the initial reactive screening test, as recommended by the World Health organisation.”
This is a far cry from the claim that the Western blot has been banned because it is completely unreliable.
Posted by: Chris Noble | March 19, 2007 03:31 AM ”
I never said that the Western Blot had been banned but it is not used in standard “diagnosis” in PHLS labs and has not been since 1992 that is a fact. It may be used very rarely on some of the less than 60 cases per year where the person who has tested “positive” on Elisa and belongs to a low risk group I.E. The average number of white, non drug using , heterosexuals thought to have “developed” “hiv” antibodies in the UK without exposure to a risk group has averaged for the last ten years around 55 cases per year with no signe of increase. Reference available from very “orthadox” drug company funded source.
In standard diagnostic settings the western blot is NOT used in England and Wales has has not been used in standard “diagnostic” setting here since 1992. I help make a banned channle 4 dispatches programe with Meditel TV productions and Continuum Magazine London , in which my flat mate Peter Nichols tested strongly reactive/”positive” on six Elisa “hiv” antibody test kits at a leading London School of medicine who was aware that these tests where being done for a television programe. We later filmed him coming out of the Royal Free Hospital London with “hiv” “negative” results. Which where repeated by poor distressed Peter with further “negative” results.
In an hour long conversation with Dr Phillip Mortimor he explained that if you pulled a handfull of “normal” people of the street 1 in 3 would have 1, 2, 3 or more bands detectable on westrn blot.
Bearing in mind that around the world varying criteria is used to define a “positive” “hiv” western blot result and that in many places in Africa or certain times and studies in the USA very low numbers of bands are/where required to define a “positive” when its well known that many “risk-group” populations have endemic causes of “cross-reactions”.
Instandard “diagnostic” settings in England and Wales algo rythams of different Elisa “hiv” test kits are used, but there is NO national standard algo rytham of Elisa test kits in England and Wales with different labs and different regions employing different algo rythams of “hiv” elisa antibody test kits. I have never said that the western Blot is banned in England and Wales but in standard “diagnostics” it is NOT used , but risk group information which does go to the lab with the blood specimen is.For the last 10 years the incidence of non risk group exposed white heterosexuals who “contracted” “hiv” in the UK has averaged around 55 cases per year.
If you go to a private doctor or lab as I have done and ask them to perform a western blot blind without elisa even after telling them its not been used for “diagnostic” purposes they all refuse point blank.
“The exceptions are Africa and England. According to Philip Mortimer, the
“Western blot detection of HIV antibodies” which is used in most countries to prove HIV infection, “began as, and should have remained, a research tool”39 and should not be used to prove infection with HIV.
http://216.239.59.104/search?q=cache:8LrJKUQkhzgJ:www.healtoronto.com/wbchart.pdf+The+fallibility+of+HIV+
western+blot.&hl=en&ct=clnk
&cd=2&gl=uk
“5 of the 220 blood donor specimens [non-reactive on ELISA] were reported to contain anti-HTLV-III [HIV antibodies]…In the high risk group 73 specimens were reported to contain anti-HTLV-III [one believed false positive]…67 reacted against both p24 and gp41, 3 against p24 only and 3 against gp41 only…In this study 6 out of 11 specimens reacting with only one of these two bands [p24, gp41] gave apparently false-positive results [on Western Blot]”
Mortimer PP et al. Which anti-HTLV-III/LAV assays for screening and confirmatory testing?. Lancet. 1985;2:873-7.
PLEASE NOTE THE WORD SUBJECTIVE OPPOSITE OF OBJECTIVE
“Interpretation of Western blots is subjective…these test have never been submitted to the rigorous evalulations and perfomance assessments under routine laboratory conditions that the screening tests for anti-HIV [e.g. ELISA] have undergone.”
Mortimer PP. The AIDS virus and the HIV test. Med Int. 1988;56:2334-9.
“Inhabitants of certain regions may have cross-reactive antibodies to locall prevalent non-HIV retroviruses”
Mortimer PP. The AIDS virus and the HIV test. Med Int. 1988;56:2334-9
“Diagnosis of HIV infection is based almost entirely on detection of antibodies to HIV, but there can be misleading cross-reactions between HIV-1 antigens and antibodies formed against other antigens, and these may lead to false-positive reactions. Thus, it may be impossible to relate an antibody response specifically to HIV-1 infection…Ideally, bands should be seen [on the Western Blot test] at least at p24, p31 and gp41, gp120 or gp160 before a serum specimen is regarded as anti-HIV positive. Indeterminate results in which only one or two bands are seen are not uncommon [proving that no single antigen/antibody reaction is conclusive proof that HIV is present]”
Mortimer PP. The AIDS virus and the HIV test. Med Int. 1988;56:2334-9
As for Western Blot giving “false-positive” in 1 in 250,000 thats nonsense as are the other figures listed, I will dig out refrences that contradict these claims.
The test like many others is approved by FDA for “diagnostic” purposes, claimed like most “hiv” antibody test kits to be 99.8% specific, but out of 250 “true” “positives” 49 are “false -positive” thats approx 1 in 5 “false positive” rate and thats when the test kit was been used by trained staff. But then again the inserts any any “hiv” antibody test, p24 test, PCR DNA/RNA test all have disclaimers that he patients never see saying words to the effect this test kit cannot be used alone to “diagnose” “hiv-infection”.
http://content.nejm.org/cgi/content/full/354/5/437
OraSure reports a test sensitivity of 99.3 percent and a specificity of 99.8 percent, but recently public health officials in San Francisco, Los Angeles, and New York reported high rates of false positive results at a few sites. In 2005, San Francisco public health clinics ran 9400 tests, of which 250 were positive. On confirmatory testing, approximately 49 appeared to be false positive. Officials were aware of the risk of false positive results, particularly in areas with a low incidence of HIV infection, but this was a higher rate than expected in a high-risk population.”
“Not only have I read Duesberg’s articles but I have checked his claims with the ‘orthodox’ literature. It is only after this that I concluded that duesberg is full of crap.”
And therefore everyone reading this blog should take Chris Noble’s word for it.
Just like everyone takes nature‘s and Science‘s “word for it” when they also say Duesberg is full of crap.
My guess is that (unlike Chris Noble) 99% of people who take [fill in the blank]’s “word for it” have not actually taken time to examine the “dissident literature” (or even the “orthodox literature” which dissidents allegedly “cherry-pick” and “abuse”).
My guess is, 99% of people who dismiss dissidents out of hand do so simply because “everyone else thinks so…”
And then everyone wonders why it’s NOT impossible for such a blunder to have happened…
Jake
In responce to Jake:
“BTW, to the person who listed all those remarkable studies on “HIV drugs”, most of those if I remember used CD4 counts or viral load as surrogate markers. Do you remember reading the quotes I posted above earlier?? Even the orthodoxy admits now that CD4 counts and viral load numbers are practically WORTHLESS.
I was expecting (hoping) maybe the quality of blog poster here would be slightly better than…other well-known blogs at this site to encounter this issue (no names, of course…)
Guess my hope was in vain…”
If you actulay read those “remarkable” studies in those links I left and read my comments you will see that I stated in all the threads that “viral-load” does not predict “cd4” and “cd4” does not predict disease or death. The studies like the L carnite study shows that “CD4” is DISASSOCIATED with “viral-load” and if you go to the banned BMJ online debate you will see that I argued these precise points and gave evidence of this in 2003. Also you will find the papers that you quoted here in the threads of “the remarkable” studies you refer to.
In Repley to:
“Linus Pauling’s vitamin C pseudoscience.
Posted by: Chris Noble | March 13, 2007 12:09 AM ”
Linus pauling is a double Nobel prize winner his vitamin C “pseudoscience” has actulay recentley had evidence supporting his position done by National Institute of Health (USA) and published in The National Acadamy of Sciences in 2005.
MAJOR BREAKTHROUGH REPORT
INTRAVENOUS VITAMIN C KILLS CANCER CELLS
Recall how hydrogen peroxide is poured on wounds to kill germs. Well now researchers clearly show high-dose vitamin C, when administered intravenously, can increase hydrogen peroxide (H2O2) levels within cancer cells and kills them. I.V. vitamin C was also demonstrated to kill germs and may be an effective therapy for infectious disease.
With a growing body of evidence mounting, National Institutes of Health (NIH) researchers conceded today that intravenous vitamin C may be an effective treatment for cancer. Last year the same researchers reported a similar study but the news media failed to publish it.
The latest study, published in the Proceedings of the National Academy of Sciences, confirms the work of Nobel-Prize winner Dr. Linus Pauling who conducted cancer research in the 1970s with vitamin C. Dr. Pauling’s studies were discredited at the time by poorly conducted research studies at the Mayo Clinic.
Unlike cancer drugs, I.V. vitamin C selectively killed cancer cells, but not healthy cells, and showed no toxicity. The ability of intravenous vitamin C to kill lymphoma cells was remarkable – almost 100% at easily achievable blood serum concentrations.
[Chart Shows High-Dose Intravenous Vitamin C Killed Almost All Lymphoma Cancer Cells.]
For inexplicable reasons, NIH researchers continue to maintain high-dose oral vitamin C can produce a limited increase in serum vitamin C concentrations. However, their earlier study published in 2004 clearly showed oral-dose vitamin C can achieve three times greater blood concentration than previously thought possible, a fact which negates the current Recommended Dietary Allowance for vitamin C. [Annals Internal Medicine 140:533-7, 2004] NIH researchers refuse to issue a retraction of their earlier flawed research which mistakenly claimed humans cannot benefit from high-dose oral vitamin C supplements.
The NIH also offered no explanation why it has taken 35 years to confirm the work of Dr. Linus Pauling. ###
-Copyright 2005 Bill Sardi, Knowledge of Health, Inc.
High Doses of IV Vitamin C Fight Cancer
MONDAY, Sept. 12 (HealthDay News) — High doses of vitamin C administered intravenously can fight cancer — at least in the laboratory, researchers report.
They took another look at the vitamin years after studies first suggested in the 1970s that high doses of ascorbate or vitamin C may help fight cancer. In the wake of those studies, additional studies using the same high doses found no benefit, although some of them used only oral vitamin C, not intravenous doses of the vitamin.
After those initial, failed studies using oral vitamin C, “the conclusion was that this therapy should be shelved, that it doesn’t work,” said lead researcher Dr. Mark Levine, chief of the molecular and clinical nutrition section and senior staff physician, National Institute of Diabetes & Digestive & Kidney Diseases.
But Levine and his team took another look at the therapy after working for the federal government on the latest recommended daily intake levels for vitamin C.
As part of those studies they examined the body’s absorption of the nutrient and found that while oral intake does reach a saturation point, “when you give doses intravenously they go through the roof in the blood and then they are cleared,” Levine explained.
According to Levine, a 10 gram dose (10,000 milligrams) of vitamin C given intravenously produces bloodstream concentrations more than 25-fold higher than concentrations achieved from the same oral dose.
Some antibiotics are poorly absorbed when given orally but fight infections effectively when given intravenously, and Levine and his team thought that might be the case with vitamin C and cancer.
Working with cell lines in the laboratory, they used high doses of vitamin C that could only be achieved by IV administration.
“At the highest concentration of ascorbic acid, if given intravenously, they don’t touch normal cells and they kill lots of cancer cells. We don’t know why,” Levine said.
According to the study, published in the Sept. 12-16 issue of the Proceedings of the National Academy of Sciences, vitamin C led to the formation of hydrogen peroxide, a chemical that can kill cells. This suggests a potential mechanism for therapy, Levine said.
“The mechanism has to be validated in animals — the effects tested in animals to see if this is true,” he said.
The newest study will likely set off another round of investigations about vitamin C’s cancer-fighting ability, said Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society. He called the study interesting and noted that it was conducted by respected scientists.
However, he said, laboratory findings are a long way from clinical practice and more study is needed. But the American Cancer Society, after careful evaluation, does note the value of dietary vitamin C in reducing cancer risk, stating that “vitamin C may have a protective role” in reducing the risk for many types of cancer when it is consumed as part of a prudent diet.
If alternative medicine practitioners — who have continued to use vitamin C treatments for cancer — provide evidence that it works, this would be the ideal time to step forward with their findings, Lichtenfeld said.
In another study published in the same issue of the journal, researchers from Pennsylvania State University found that retinoic acid, also known as vitamin A, can boost immune system functioning, at least in mice.
Researchers A. Catharine Ross and Yifan Ma found that injecting mice with the vitamin boosted their production of natural killer cells after they got a tetanus vaccine, improving their immune system response.
Newborns are susceptible to infectious diseases, and because their immune systems are immature often respond poorly to vaccines. Adding the vitamin A may help, although further study is needed, the researchers said.
Published online before print September 12, 2005
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0506390102
Medical Sciences
Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues
Qi Chen *, Michael Graham Espey , Murali C. Krishna , James B. Mitchell , Christopher P. Corpe *, Garry R. Buettner , Emily Shacter , and Mark Levine *¶
*Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IA 52242-1101; and Laboratory of Biochemistry, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
Communicated by J. E. Rall, National Institutes of Health, Bethesda, MD, August 2, 2005 (received for review June 1, 2005)
Human pharmacokinetics data indicate that i.v. ascorbic acid (ascorbate) in pharmacologic concentrations could have an unanticipated role in cancer treatment. Our goals here were to test whether ascorbate killed cancer cells selectively, and if so, to determine mechanisms, using clinically relevant conditions. Cell death in 10 cancer and 4 normal cell types was measured by using 1-h exposures. Normal cells were unaffected by 20 mM ascorbate, whereas 5 cancer lines had EC50 values of <4 mM, a concentration easily achievable i.v. Human lymphoma cells were studied in detail because of their sensitivity to ascorbate (EC50 of 0.5 mM) and suitability for addressing mechanisms. Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis and pyknosis/necrosis. Cell death was independent of metal chelators and absolutely dependent on H2O2 formation. Cell death from H2O2 added to cells was identical to that found when H2O2 was generated by ascorbate treatment. H2O2 generation was dependent on ascorbate concentration, incubation time, and the presence of 0.5-10% serum, and displayed a linear relationship with ascorbate radical formation. Although ascorbate addition to medium generated H2O2, ascorbate addition to blood generated no detectable H2O2 and only trace detectable ascorbate radical. Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H2O2, and that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H2O2 may be beneficial.
Also the personal attacks and character assination of the inventor of PCR and 1993 Nobel Prize winner Dr Kerry mullus are below the belt and childish , and please remember “hiv” “viral-loads” are bastardised forms of PCR. But then again “viral-loads” of been discredited as “predictive” surrogate markers.
I dismiss dissidents because I have taken the trouble to look in detail at their claims, and found them wanting. In fact the more I search the literature for corroborating evidence for their claims, the more I find they have used a combination of mis-attribution, misquotation, quote mining, cherry-picking, and deviousness in attempting to put put their case.
Crucially, denialists ignore evidence that contradicts their own preconceptions. If there is one paper expressing doubt about the validity of a particular assay, this paper will be repeatedly championed as though it gives the final word on the topic. Dozens of other papers may exist in the literature which express a definitive view – but these papers will be deliberately ignored by the denialists, even when they are asked to comment on them. They are sometimes shamed into silence for a few days until the nasty questions are forgotten, only to pop up annoyingly again like a bizzare game of “whack-a-mole” touting the same paper again as “proof” for their viewpoint, in the hope they can convince any new visitors to the web site as to the “overwhelming evidence” that supports their cause.
True science actively searches for evidence that contradicts hypotheses. If the best “evidence” against HIV is the mish-mash of what is called science from the Perth Group/virusmyth, then no wonder the status quo remains firm.
Seeing for myself how insubstantial the denialist position is has merely strengthened my own opinions on the matter, not cast further doubt on it.
in reply to :Posted by: DT | March 26, 2007 08:32 AM
Like alot of “aids” “science” your reply is NON specific.
It consists ONLY of character assisnation.
Your reply has no scientific content, no references, no supporting scientific evidence , no specific scientific points , no scientific question, no scientific answer and did not address any specific , point, evidence, reference, study, experiment, paper, question , person, theory presented here.
It just calls people silly, insultive, misrepresentative, names like “denialists”
You do not answer or address or question published studies on glutathione/nac/antioxidants reversing, inhibiting KS in vito, in vivo and succesfully inhibiting TB in vitro in vivo ,TB which is Africa’s number ONE “aids” defining disease.
You do not address the old evidence from “orthadox” researchers or the new evidence from two “orthadox” leaders that disprove the lynch pin of the “hiv” kills “cd4’s” = causes “aquired immune defiency” thus causes the syndromes that can be called “aids” theory/religion .
I.E. “viral-load” predicts “CD4″,”cd4” predicts disease and death.
You do not address that glutathione, selenium levels do predict disease and death in people with “hiv” and more so people with “aids”. eg Selenium defiency in IV drug users predicts a 13 fold higher incidence of TB.
In your reply you say :
“True science actively searches for evidence that contradicts hypotheses “.
Yet your reply contained no evidence ?
it didnt address any of the scientific evidence,experiments,papers,studies presented ?
It didnt contain any science or any scientific point at all ?
I thought true science was and should be based on respectfull, open,civilized, adult, free, debate, being able to ask questions, presenting , addressing, examining, evidence, experiments, studies, papers not ignoring them.
Why doesnt your good scientific self or Mr Nobel or any other defenders of the “hiv” singulary causes “aids” religion/theory provide a decent scientific answer that holds water and has evidence to:
1.If one experiment/model using a gene from “hhv-8” to cause -induce “ks-like” lessions proves/”firmly establishes” “hhv-8” as the cause of KS why dont two animals experiments/models of causing/inducing “KS like lessions” and more that did not have, involve, or contain “hhv-8” disprove/dis-establish that “hhv-8” is the cause of KS theory?
2.Can you explain why , if “hhv-8” plus “hiv” is the cause of Kaposi Sarcoma the original/siginal “aids” defining disease there is a minute, pathetic, very rare 0.2% incidence of KS in Thailand when there is a high incidence/seroprevelance comaparable with gay/bi of “hhv-8” and a “hiv” and “aids” epidemic in Thailand but the incidence of Kaposi Sarcoma in gay/bi men in the early 1980’s was 35% to 55% of “aids” cases in the USA , west and Europe ? Thats a gigantic difference why ?
can anyone answers these two questions please with evidence that relates to these studies.
Just to remind you, Mr Christopher Nobel stated:
“J,
Gallo and others knew a long time before 1994 that HIV was not the direct cause of KS. It was proposed fairly early that KS was caused by another sexually transmitted microbe by Valerie beral and others.
HHV-8 was subsequently discovered and its role in the pathogenesis of KS is firmly established with epidemoiolgy and animal models to support it.
HIV is believed to increase the risk of getting KS by a) immune suppression and b) HIV-tat activation of HHV-8.”
I replied:
http://groups.msn.com/AIDSMythExposed/general.msnw?action=get_message&mview=0&ID_Message=27986&LastModified=4675614897007893766
Please note there are 3 animal models of inducing KS “like” legions and 2 of them didnt contain “hhv-8”. The one that did contain “hhv-8” was supplied by Mr Noble during the banned BMJ debate.
Not only does the Thailand “hhv-8” seroprevence study show a high incidence of “hhv-8” more or less the same as gay/bi men in USA,West and Europe with a minute very rare incidence of KS 0.2% campared with 35%-55% KS incidence in gay/bi men in US, West and Europe, they also state “hhv-8” is not sexually transmited.
The published references are quoted in full (to make sure nobody from the “hiv” religion accuses me of misquoting, misrepresenting as they usually do when evidence presented disproves there theory/religion which they think nobody has a right to question )
I wonder if I will get scientific answers to my two questions that actually answer this massive contradiction from the defenders of the “hiv” faith/religion/theory ?
I didnt get any propper or valid answer that is scientific or holds water in the banned BMJ debate will Mr Nobel or any other “hiv” defender of the faith answer my two simple questions now or just continue to ignore them and the studies ?
DT said:
“I dismiss dissidents because I have taken the trouble to look in detail at their claims, and found them wanting”.
DT, as with most of what you have to say, that statement of yours is not true at all!
DT dismisses the HIV dissidents because DT is a HIV drug rep to doctors for a pharmaceutical company! Doooohhhh!
In reply to jake,
I just wanted to clarify my position on “low-cd4” , I have stated it hundreds of times on the internet but sometimes people some how misunderstand my position on “cd4” which is in my opinion it is not causative, not predictive of “aids” but is a possible “symptom”, possible side effect of disease causing mechanisms.
Sorry I got the date wrong it was 2005 not 2003 I argued that “viral-load” does not predict “cd4” and that a dissociation between “viral-load” and “cd4” existed and that “cd4” was not a good predictor of disease or death and not the cause of many “aids” diseases. In the links I left earlier it shows people on “succesfull” combination therapy having relaspes/out breaks of Kaposi sarcoma despite having between 350 “cd4” and above “normal” levels of “cd4” 1300+ “cd4” with virtualy “undetectable” “viral-loads” so I guese that means there not much “hiv” tat about either. The links also demonstrate “aids” diseases getting better before and without rises in “cd4” and before declines of “viral-load” and that “cd4” is raised by P.I’s before “viral-load” drops and even after “viral-resistance-viral-increase-rebound”.
I have re checked and indeed the “orthadox” studies you posted here are posted in two out of 3 of the “remarkable” studies/links that I left earlier showing that “viral-load” does not predict “cd4” and that “cd4” does not predict disease, “aids” or death and that “arv’s” are non specific.
I didnt get an answer to my questions in 2005 about “hhv-8” in Thailand that was scientific or answered the massive contradiction from either Mr Nobel or Nicholas Bennett or any other person and I wont hold my breath waiting for an answer now either to that question or the question of how come two out of three animal models of inducing Kaposi sarcoma “like” lessions didnt contain “hhv-8” and the best model that induced tumours didnt contain either “hiv” or “hhv-8”.
“Re: Re: Yet More on Oxidation – the primary cause for AIDS and “HIV” 29 March 2005
James J Whitehead,
Send response to journal:
Re: Re: Re: Yet More on Oxidation – the primary cause for AIDS and “HIV”
Dear Nicholas Bennett,
In Reply to :
“Fundamentally, the CD4 count is a measure of how far the train is from the end of the tracks (AIDS) and the viral load is a measure of how fast the train is travelling. ”
KS the original signal disease of “aids” has got nothing to do with CD4.
And the largest and longest AZT monotherapy trial showed:
“AZT ran into more serious difficulties with the European Concorde trial, which showed (and continues to show) no clinical benefit from the use of the drug but increased mortality in a group taking AZT early after an “HIV” diagnosis. Panorama interviewed the members of the British Medical Research Council involved in the Concorde trial and learnt of the problems they experienced with the company.”
“At the start of the trial, the MRC team revealed, the company had wanted to use CD4 cell counts as an indicator of the drug’s success. The team refused to allow this, suspecting that CD4 counts could be raised by the action of the drug without offering any health benefits. “We were worried that the CD4 count might be a cosmetic measure,” Concorde’s U.K. Chairman Prof. David Warrell explained. This turned out to be correct. In the latest analyses of the Concorde data, raised CD4 cell counts are found in the group, with higher mortality, starting AZT early. ” (1) Please also note that I was present and witnessed and filmed the emergency “fixed” meeting at Glaxo Wellcome’s head offices in Euston Road London where Glaxo Wellcome’s tried to muddy the waters about the UK MRC Concorde trial results.
Also as Eleni and the Perth group presented several studies showing that AZT given to hiv negatives causes a very significant increase in CD4, nothing to do with there non existant “viral-loads”. IE.
“We and others (Rapid Responses for Mhlongo and Maduna http://bmj.bmjjournals.com/cgi/eletters/328/7438/523-b#55304) have presented evidence that the increase in T4 cells by antiretrovirals, if any, may be due to a mechanism unrelated to any “HIV” effects. If the increase in T4 cells in “HIV” infected individuals is due to an effect on HIV replication then how does Nicholas Bennett explain the increase of T4 cells by AZT in non-infected individuals? Which may approach double over pre-treatment levels? See
1. Levy JA, Ramachadran B, Barker E, Guthrie J, Elbeik T. Plasma viral load, CD4+ cell count and HIV-1 production by cells. Science 1996;271:670-671.
2. Milazzo L, Vaira LM, Cremoni L. CD4+ lymphocyte count variations in HIV-negative subjects treated with zidovudine. AIDS 1996;10:1444-5. ”
And again can I refer Nicholas to the study everyone in science and medicine chooses to ignore that I presented in my rapid responce.(“Re: Re: More on Oxidation – the primary cause for AIDS and “HIV”, 7 February 2005). The study that shows 100% to 200% increases in CD4 with no change in “viral-load” or even with an increase in “viral-load”.
“”Taken together, our data suggest that long-term L-carnitine administration may have a substantial impact on the chief immunologic abnormality associated with HIV-1 infection, the loss of CD4 T cells, through downmodulating the generation of ceramide and reducing the rate of apoptotic lymphocyte death, without affecting the HIV-1 viremia levels, thus suggesting that a dissociation exists between changes in viremia and CD4 depletion.” (2)
In reply to:
“Now that the Montagnier graph has been fixed, it appears that the interpretation has also been “fixed”.
The graph was not fixed nor was the interepretation. Again I filmed and photographed the Conference and paid particular attention to Prof Luc Montaigniers speech and graphs. The graph shown is exactley how it appears in an EEC produced book. There are other graphs which I hope to present at a later date which neatley also demonstrate that a disassociation between CD4 and “viral-load” can and does exist when ARV therapy is not being used.
In reply to:
“Do they accept the National Cancer Institute’s statement that Kaposi’s Sarcoma is massively increased in frequency in immunosuppressed people?””
When “aids” first came out in the early 1980’s approx 30% to 40% of “aids” cases presented with Kaposi Sarcoma (please note 97% to 100% of the “aids” Kaposi Sarcoma cases occured in gay men not other “aids” risk groups, best not to lump all the KS cases together under “aids” because that neatley distorts the true picture that “aids” KS in the west is a specific disease of gay men and is there for it is very misleading to lump all the “aids” KS cases together without stating all the cases or nearly all the “aids” KS cases are in gay men and not other “aids” risk groups.
The studies I have already presented about KS, show that there is only a minute 0.2% incidence of KS in Thailand despite an “aids” epidemic (one presumes they are immunosuppressed) and despite a high back ground of HHV-8. We are also told that KS decined because of the introduction of HAART , however the sharp decline in KS cases started 10 years before HAART came out and in Thailand HAART is not available.
Your reply to the Thailand and italian studies I presented was “well that not what we see here in the US”.
Well with all due respect that answer is not in anyway convincing to me nor should it be to any scientist or doctor. Also we are told iatrogenic KS occurs more frequentley in Saudi Arabia and Turkey in transplant recipients due to the higher seroprevelance of HHV-8. However the numerouse studies I have presented already show that this is not the case with 50% of the control group in Italy having HHV-8 and 26 % of texas school children having HHV-8. I am astounded that any scientist or doctor thinks that KS is caused by low CD4, when all the available eveidence shows that low CD4 is neither sufficient to cause KS nor is a low CD4 required for KS to occur. IE. KS can occur in people with perfectley normal CD4. So the original signal disease of “aids” is not caused by Immune Defiency, there for it is not “aids”.
Best Wishes
James J Whitehead
Clinical Trials volunteer
Member http://www.altheal.org and http://www.aidsmythexposed.com
References 1.BBC (“Panorama”) Expose on AZT/Wellcome
BBC Panorama Documentary Programme “A Ray of Hope”, 40 mins. http://www.sumeria.net/aids/expose.html
2.Blood, Vol. 91 No. 10 (May 15), 1998: pp. 3817-3824. Effect of L- Carnitine on Human Immunodeficiency Virus-1 Infection-Associated Apoptosis: A Pilot Study. By Sonia Moretti, Edoardo Alesse, Luisa Di Marzio, Francesca Zazzeroni, Barbara Ruggeri, Sonia Marcellini, Giuseppe Famularo, Seth M. Steinberg, Antonio Boschini, M. Grazia Cifone, and Claudio De Simone .
Competing interests: Clinical trial volunteer member http://www.altheal.org ”
For a link to a graph presented to the European Parliament meeting in 2004 by the real discover of “hiv” Prof Luc montaignier, presented in the BMJ debate by Eleni and the Perth Group in 2005 before the debate was censored and banned once the good editor Richard left. The graph shows no corralation between “viral-load” and “cd4” exactley what “orthadoxy” is saying themselfs now, and exactley what they censored and insulted good scientists for stating, presenting evidence showing they where wrong.
http://www.rethinking.org/bmj/response_101165.html
Which “side” wants to deny debate, which “side” wants to deny free speech, which “side” wants to deny questions ? Which “side” calls for censorship of media, scientists, patients, doctors, journalists,who are the real “denialists” then ?
Science stops being science when debate, free speech and questioning is not allowed , it becomes nothing more than a religion.
The lunacy continues, it seems. Peripheral blood CD4 T cell counts are a surrogate marker for the loss of CD4 T cell function that actually allows opportunistic pathogens to escape immune control and cause disease. Some HIV-negative people with HHV8 display low T cell responses to HHV-8 in the absence of low peripheral blood T cell counts and this is associated with the development of Kaposi’s sarcoma. However, CD4 T cell counts remain a reasonably good surrogate marker for the loss of HHV8-specific T cell immunity in people with HIV and hence Kaposi’s sarcoma is more common in people with low peripheral blood CD4 T cell counts (the association is not absolute however). You can go down the list of opportunistic pathogens and look at studies showing that clinical disease is associated with the loss/dysfunction of the relevant pathogen-specific T cell response. This is because HIV infection leads to progressive dysregulation of the pools of memory CD4 T cells, CD8 T cells and B cells (of which the shrinking of the repertoire of these cells is a tell-tale sign). The mechanism – which many AIDS denialists seem to think should be obvious (they seemingly have no idea how complex T cell homeostasis is) – is likely related to persistent immune activation, since this leads to the accumulation of HIV-specific dysfunctional memory T cell responses (and other dysfunctional memory T cells such as those displaying a double negative CD4-CD8- phenotype) at the expense of pre-existing memory T cells (targeting pathogens such as CMV, for example).
If Margulis really wants insights into HIV, she should talk to a cellular immunologist (Judy Lieberman is close by, as is Bruce Walker). In fact, does anyone know of a single working cellular immunologist who argues that HIV does not cause AIDS? I certainly don’t.
J Infect Dis. 2006 Oct 15;194(8):1078-88. Epub 2006 Sep 15.
Low T cell responses to human herpesvirus 8 in patients with AIDS-related and classic Kaposi sarcoma.
Guihot A, Dupin N, Marcelin AG, Gorin I, Bedin AS, Bossi P, Galicier L, Oksenhendler E, Autran B, Carcelain G.
Laboratoire d’Immunologie Cellulaire et Tissulaire du Pr. Debre, INSERM UMR S 543, Batiment CERVI, Hopital Pitie-Salpetriere, 47 bd de l’hopital, 75013, Paris, France.
BACKGROUND: Kaposi sarcoma (KS) occurs mainly in immunocompromised patients and is strongly associated with infection with human herpesvirus 8 (HHV-8; also known as “KS-associated herpesvirus”). We hypothesized that KS is linked to deficiencies in specific anti-HHV-8 T cell immunity. METHODS: We studied asymptomatic HHV-8 carriers coinfected with human immunodeficiency virus (HIV; n = 23) and patients with HIV-related or classic KS (n = 29). We used an interferon- gamma enzyme-linked immunospot assay with 56 specific peptides distributed on 6 HHV-8 proteins (glycoprotein [gp] B, gpH, gp35/37, latent nuclear antigen 1 [LANA-1], K12, and K15) to detect HHV-8-specific T cell responses. RESULTS: We found that patients with KS responded to these peptides less often and had much lower HHV-8-specific T cells counts than did asymptomatic HHV-8 carriers (P = .001 and P = .0004, respectively), regardless of CD4 T cell count or HHV-8 load. The frequency of Epstein-Barr virus-specific T cells was similar in both groups. CONCLUSIONS: Our results suggest that HIV-related and classic KS are associated with a lack of HHV-8-specific T cells. Also, we have described 8 new HHV-8 T cell epitopes in LANA-1, K12, and K15, including 2 CD4 T cell epitopes. These data provide new insight into HHV-8 cellular immunity.
PLoS Med. 2007 Mar 27;4(3):e96 [Epub ahead of print]
HIV Patients Developing Primary CNS Lymphoma Lack EBV-Specific CD4(+) T Cell Function Irrespective of Absolute CD4(+) T Cell Counts.
Gasser O, Bihl FK, Wolbers M, Loggi E, Steffen I, Hirsch HH, Gunthard HF, Walker BD, Brander C, Battegay M, Hess C; for the Swiss HIV Cohort Study.
BACKGROUND: In chronic HIV infection, antiretroviral therapy-induced normalization of CD4(+) T cell counts (immune reconstitution [IR]) is associated with a decreased incidence of opportunistic diseases. However, some individuals remain at risk for opportunistic diseases despite prolonged normalization of CD4(+) T cell counts. Deficient Epstein-Barr virus (EBV)-specific CD4(+) T cell function may explain the occurrence of EBV-associated opportunistic malignancy-such as primary central nervous system (PCNS) lymphoma-despite recovery of absolute CD4(+) T cell counts. METHODS AND FINDINGS: Absolute CD4(+) T cell counts and EBV-specific CD4(+) T cell-dependent interferon-gamma production were assessed in six HIV-positive individuals prior to development of PCNS lymphoma (“cases”), and these values were compared with those in 16 HIV-infected matched participants with no sign of EBV-associated pathology (“matched controls”) and 11 nonmatched HIV-negative blood donors. Half of the PCNS lymphoma patients fulfilled IR criteria (defined here as CD4(+) T cell counts >/=500/mul blood). EBV-specific CD4(+) T cells were assessed 0.5-4.7 y prior to diagnosis of lymphoma. In 0/6 cases versus 13/16 matched controls an EBV-specific CD4(+) T cell response was detected (p = 0.007; confidence interval for odds ratio [0-0.40]). PCNS lymphoma patients also differed with regards to this response significantly from HIV-negative blood donors (p < 0.001, confidence interval for odds ratio [0-0.14]), but there was no evidence for a difference between HIV-negative participants and the HIV-positive matched controls (p = 0.47). CONCLUSIONS: Irrespective of absolute CD4(+) T cell counts, HIV-positive patients who subsequently developed PCNS lymphoma lacked EBV-specific CD4(+) T cell function. Larger, ideally prospective studies are needed to confirm these preliminary data, and clarify the impact of pathogen-specific versus surrogate marker-based assessment of IR on clinical outcome. Blood. 2005 Nov 1;106(9):3166-74. Epub 2005 Jul 12. Loss of EBNA1-specific memory CD4+ and CD8+ T cells in HIV-infected patients progressing to AIDS-related non-Hodgkin lymphoma. Piriou E, van Dort K, Nanlohy NM, van Oers MH, Miedema F, van Baarle D. Department of Clinical Viro-Immunology, Sanquin Research at CLB and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, The Netherlands. We previously observed a loss of Epstein-Barr virus (EBV)-specific CD8+ T cells in subjects progressing to EBV-related non-Hodgkin lymphoma (NHL), correlating with loss of CD4+ T cells. The aim of the present study was to determine the role of EBV-specific CD4+ T cells in the development of NHL during chronic HIV infection. To this end, CD4+ and CD8+ memory T cells, capable of both proliferation and subsequent interferon gamma (IFNgamma) production, directed against a latent (Epstein-Barr virus nuclear antigen 1 [EBNA1]) and a lytic (BamH fragment Z left frame 1 [BZLF1]) EBV antigen were studied longitudinally in 9 progressors to NHL, 4 progressors to non-EBV-related AIDS, and 4 slow progressors to AIDS. In all 3 groups we observed a decline of EBV-specific memory CD4+ and CD8+ T-cell responses during HIV infection. However, whereas latent antigen EBNA1-specific CD4+ T cells were lost well before diagnosis in all subjects who developed an AIDS-related NHL (and EBNA1-specific CD8+ T cells were significantly lower compared with the other groups), these cells were better preserved in progressors to non-EBV-related disease and slow progressors. Loss of EBNA1-specific T-cell immunity thus might be important for progression to NHL. Interestingly, BZLF1-specific T cells were not lost in all progressors to NHL, suggesting a different function of these cells in the surveillance of EBV-infected B cells. J Infect Dis. 2005 Mar 15;191(6):873-80. Epub 2005 Jan 31. Dynamics of cytomegalovirus (CMV)-specific T cells in HIV-1-infected individuals progressing to AIDS with CMV end-organ disease. Bronke C, Palmer NM, Jansen CA, Westerlaken GH, Polstra AM, Reiss P, Bakker M, Miedema F, Tesselaar K, van Baarle D. Department of Clinical Viro-Immunology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands. BACKGROUND: Since cytomegalovirus (CMV) infection can cause serious clinical complications in immunocompromised individuals, we assessed cellular immune requirements for protection against CMV end-organ disease (CMV-EOD) in human immunodeficiency virus type 1 (HIV-1) infection. METHODS: Longitudinal samples from HIV-1-infected patients in the Amsterdam cohort were analyzed. Dynamics of CMV-specific CD8(+) and CD4(+) T cell responses were analyzed by 4-color fluorescence analysis using major histocompatibility class I CMV peptide-tetramers and by intracellular staining for perforin, granzyme B, and interferon (IFN)- gamma after stimulation with CMV-specific stimuli. CMV load was measured in parallel. RESULTS: In individuals progressing to acquired immunodeficiency syndrome with CMV-EOD, CMV-specific IFN- gamma -producing CD4(+) T cells disappeared during the year before onset of CMV-EOD. This disappearance was accompanied by a sharp increase in CMV load before onset of disease. Despite increasing CMV-specific CD8(+) T cell counts, decreasing CMV-specific IFN- gamma -producing CD8(+) T cell counts were found over time. In contrast, the percentage of CMV-specific perforin- and granzyme B-expressing CD8(+) T cells increased. CONCLUSIONS: Our data indicate that insufficient help of CD4(+) T cells may cause loss of IFN- gamma -producing CD8(+) T cells and loss of control of CMV dissemination. Increasing CMV-infected cell counts in the face of high CMV-specific perforin- and granzyme B-expressing CD8(+) T cell counts may explain the immune pathological characteristics of CMV disease. J Infect Dis. 2006 Dec 1;194(11):1537-46. Epub 2006 Oct 26. Protective immunity to cytomegalovirus (CMV) retinitis in AIDS is associated with CMV-specific T cells that express interferon- gamma and interleukin-2 and have a CD8+ cell early maturational phenotype. Sinclair E, Tan QX, Sharp M, Girling V, Poon C, Natta MV, Jabs DA, Inokuma M, Maecker HT, Bredt B, Jacobson MA; Studies of Ocular Complications of AIDS Research Group. Division of Experimental Medicine, University of California, San Francisco, CA, USA. To determine potential correlates of immune recovery from AIDS-related cytomegalovirus retinitis (CMVR), multiparameter flow cytometry was used to characterize CMV-specific T cells from subjects with CMVR. Individuals with active retinitis were compared with those who had been clinically immunorestored by antiretroviral therapy and had > or =2 years of ophthalmologic follow-up without anti-CMV therapy or retinitis reactivation or progression. In comparison with patients with active retinitis, immunorestored patients had higher circulating CD4(+) and CD8(+) T cells expressing interleukin-2 and interferon- gamma in response to combined CMV pp65 and IE1 peptide pool stimulation. CD4(+) T cell responses were predominantly to pp65, whereas CD8(+) T cell responses were predominantly to IE. Immunorestored patients, compared with patients with active retinitis, had increased levels of circulating CMV-specific CD8(+) T cells with “early” (CD27(+)CD28(+)CD45RA(+), CD27(+)CD28(+)CD45RA(-)) and “intermediate” (CD27(-)CD28(+)CD45RA(-)) phenotypes. Recovery from AIDS-related CMVR after the initiation of antiretroviral therapy may be mediated by CMV-specific CD4(+) and CD8(+) T cells capable of promoting antigen-specific CD8(+) T cell proliferation.
AIDS. 2003 Jul 4;17(10):1443-9.
Critical role of JC virus-specific CD4 T-cell responses in preventing progressive multifocal leukoencephalopathy.
Gasnault J, Kahraman M, de Goer de Herve MG, Durali D, Delfraissy JF, Taoufik Y.
INSERM E-0109, AP-HP, CHU de Bicetre, France.
BACKGROUND: JC virus (JCV) is ubiquitous among the general population. However, only individuals with severely impaired immunity, mainly AIDS patients, develop progressive multifocal leukoencephalopathy (PML). Here, we examined the role of specific CD4 T cells in the control of JCV infection. METHODS AND DESIGN: JCV-specific CD4 T-cell responses were investigated by assaying peripheral blood mononuclear cell proliferation in response to the purified virus. Four groups of individuals without PML were examined: 14 HIV-seronegative healthy donors and 25 HIV-infected patients without PML, separated into urinary JCV excretors (active infection) and non-excretors, according to JCV PCR on urine. Two groups of patients with PML were also studied: 14 HIV-infected patients with active PML; and 10 PML survivors on effective and prolonged antiretroviral therapy. All of the patients were PCR-positive for JCV in the cerebrospinal fluid at the time of diagnosis of PML. RESULTS: No significant anti-JCV CD4 T-cell proliferation was found in any of the non-excretors tested. All nine healthy donors and seven of the 13 non-PML HIV-infected patients with urinary JCV excretion had positive JCV-specific CD4 T-cell responses. No significant response was found in the 14 patients with active PML, while nine of the 10 PML survivors had positive responses. Restoration of JCV-specific CD4 T-cell responses was associated with JCV clearance from the cerebrospinal fluid. CONCLUSION: JCV-specific CD4 T-cell responses appear to play a critical role in the control of JCV infection, preventing PML development. Such responses can be restored in PML survivors following effective and prolonged antiretroviral therapy.
J Clin Lab Immunol. 1989 Apr;28(4):179-82.
Impaired in vitro lymphocyte response to toxoplasma antigen in HIV1 infected patients.
Derouin F, Rabian-Herzog C, Ballet JJ.
Laboratoire de Parasitologie Mycologie, Inserm U 108, Hopital Saint-Louis, Paris, France.
The containment of Toxoplasma gondii infection is largely dependent of T cell mediated immunity. In this study, in vitro lymphocyte responsiveness to T. gondii antigen was examined in 59 HIV1 infected individuals and in 58 HIV non-infected controls. Of the 45 patients with serological evidence of past Toxoplasma infection, a significant proliferative response was found in only 18, whereas responses were present in 48 out of 51 controls with anti-Toxoplasma antibodies. In the 27 non-responder patients, the lack of proliferative response to T. gondii antigen was correlated with the loss of CD4+ cells, and the impairment of proliferative responses to other microbial antigens, whereas responsiveness to phytohaemagglutinin and concanavalin A were not significantly diminished. Results are consistent with impairment of cell mediated immunity to T. gondii in patients at risk for reactivation of chronic Toxoplasma infection. Of note, in the one year clinical following, 2 of the 27 non-responder patients developed toxoplasmic encephalitis compared to 0 of 18 with a Toxoplasma specific proliferative response.
J Infect Dis. 1988 Nov;158(5):1071-8.
Functional versus phenotypic analysis of T cells in subjects seropositive for the human immunodeficiency virus: a prospective study of in vitro responses to Cryptococcus neoformans.
Hoy JF, Lewis DE, Miller GG.
Program in Infectious Diseases and Clinical Microbiology, University of Texas Medical School, Houston.
We performed a prospective study of 50 subjects at high risk for human immunodeficiency virus (HIV) infection to determine if assays of antigen-specific T cell function provide an earlier indication of future progression to AIDS or a better assessment of immune function than do current methods of evaluation. We measured in vitro T cell responses to Cryptococcus neoformans and tetanus toxoid, response to mitogens, HIV p24 antigenemia, and clinical parameters. Progression to AIDS was significantly associated with loss of T cell response to cryptococci (P = .015), HIV antigenemia (P = .001), and low CD4+ cell numbers (P = .001). Most importantly, we found that loss of antigen-specific responses to cryptococci and tetanus can occur before changes in CD4 cell number. Abnormal response to mitogens and marked depletion of CD4+ cells were late signs of progressive HIV infection. Measurement of antigen-specific T cell function may be useful for assessing the efficacy of antiviral therapy in HIV infection before onset of symptoms.
Dear Richard,
To question the causation/s of between 24 to 29 old diseases that can now sometimes be called “aids” does not make a person a “denialist”.
Could you answer my questions please why is there only a 0.2% incidence of Kaposi Sarcoma in Thailand when there is claimed to be an “aids” epidemic ( meaning that those people must according to the theory you support be immune suppressed with low “cd4”) with a very high back ground of “hhv-8” when virtually all the KS cases in the west occured in gay/bi men who at the “start” of the “aids” epidemic had between 35% to 55% insidence of Kaposi Sarcoma with a simular back ground rate of “hhv-8” than to the Thailand study?
Why does the best Kaposi Sarcoma animal model not contain either “hiv” or “hhv-8” ?
Why does the other animal model of KS “like ” lessions induced by “hiv” tat not contain “hhv-8” if “hhv-8” is the cause of Kaposi Sarcoma ?
If “hiv” tat causes kaposi Sarcoma why are virtually all the KS cases in west confined to gay and bi men and not straight heterosexuals belonging to other high risk groups with “hiv” ?
Or does “hiv” tat just express itself in gay and bi men ?
Why does the USA Army Walter read institute say Kaposi Sarcoma is not caused by immune suppression and shouldnt be defined as “aids” ?
Or simply please could you answer my two questions above wich you have not answered ?
For starters, let’s dispense with the “old diseases” nonsense please. Anyone want to take a guess as to how many cases of CMV retinitis had been reported in the scientific literature circa 1976, prior to the advent of HIV infection? How about disseminated mycobacterium avium complex? Tip: do a PubMed search and use the function that allows you to limit the search dates.
“glutathionesurvival1,” regrettably your question makes little sense. You’re trying to make extrapolations based on epidemiological data from Thailand? Is that correct? Maybe the study authors should be consulted on the subject:
“Although we were able to determine the prevalence of HHV-8 infection in this study population, the cross-sectional nature of the data does not allow us to establish the temporal associations between various characteristics and HHV-8 infection or to determine when participants developed their infection. Thus, although HIV infection was associated with higher HHV-8 seroprevalence, we do not know whether HIV infections preceded or followed HHV-8 infections. In prospective studies examining the temporal relationship between HIV and HHV-8 infections among homosexual men, 2 groups of investigators found that men who seroconverted to HHV-8 after HIV infection had a significantly higher risk for developing KS than did those who acquired HHV-8 before HIV [5, 6]. If most of the HHV-8 infections in Thailand occurred during childhood, well before HIV-related immunosuppression, the immune system might be able to contain HHV-8 replication, even after subsequent HIV infection or AIDS, and prevent progression to KS [29]. Higher titers of HHV-8 antibody have been found in saliva than in genital secretions, suggesting that oral contact may be important in transmission [30].
Other intriguing possibilities are that HHV-8 strains in Thailand and other Asian countries are genetically different from strains in areas where KS is more common, as has been reported with respect to Brazilian Amerindians [22], or that cofactors important to the pathogenesis of KS are absent in Thailand. Perhaps there is a genetic susceptibility to KS among HHV-8-infected persons in the United States and Europe that is lacking in the Thai population. Regardless, our data indicate that the fact that KS is rare among patients in Thailand with AIDS is not because HHV-8 infections are uncommon in this population.”
Your conclusion from this is that HIV infection can’t cause KS, because it’s uncommon in Thailand despite a relatively high HHV8 prevalence, do I have that right? Doesn’t seem to be what the authors are saying. And of course the immunogenetics of the different populations being discussed in this article are vastly different. You can find thousands of studies showing how different class I and class II HLA types influence disease (including HIV, where for example HLA B57 is strongly and consistently associated with a lack of symptoms during acute infection and long-term non-progression). Associations between HLA and KS have been controversial and inconsistent, but as far as I can tell that’s because of small sample sizes. Some large-ish studies have reported associations, however, which you’d expect in the setting of a viral infection that’s primarily controlled by CD4 and CD8 T cell responses:
J Infect Dis. 2007 Mar 15;195(6):809-16. Epub 2007 Feb 5.
Influence of HLA alleles on shedding of Kaposi sarcoma-associated herpesvirus in saliva in an African population.
Alkharsah KR, Dedicoat M, Blasczyk R, Newton R, Schulz TF.
Institute of Virology, Hannover Medical School, Hannover, 30625, Germany.
BACKGROUND: Kaposi sarcoma-associated herpesvirus (KSHV) is endemic in sub-Saharan Africa. Infection in childhood involves mother-to-child transmission and transmission between siblings or other close contacts. Large amounts of viral DNA in saliva have been linked to transmission from mother to child. To investigate factors contributing to the shedding of KSHV in the saliva of mothers in rural South Africa, we sequenced the HLA-A alleles of 448 mothers and the HLA-DRB1 alleles of 363 mothers and compared their HLA types with viral loads in saliva. METHODS: Viral load was quantified with real-time polymerase chain reaction on DNA extracted from saliva. HLA-A and HLA-DRB1 allele groups were determined by sequencing-based typing. RESULTS: We found that 2 HLA-A alleles, A*6801 and A*4301, and 1 HLA-DRB1 allele group, DRB1*04, were associated with shedding of KSHV in saliva. KSHV could be detected more frequently in mothers carrying at least 1 copy of HLA-A*6801 or HLA-A*4301, and higher viral loads were found in HLA-A*68- and HLA-DRB1*04-carrying mothers. CONCLUSIONS: These findings could suggest that 2 HLA-A alleles, A*6801 and A*4301, and 1 HLA-DRB1 allele group, DRB1*04, that are more frequent in African populations might be associated with an impaired control of KSHV and, hence, increased shedding in saliva.
J Med Virol. 2005 Jul;76(3):302-10.
HLA-B, -DRB1/3/4/5, and -DQB1 gene polymorphisms in human immunodeficiency virus-related Kaposi’s sarcoma.
Dorak MT, Yee LJ, Tang J, Shao W, Lobashevsky ES, Jacobson LP, Kaslow RA.
Department of Epidemiology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0022, USA.
Polymorphisms of genes in the human leukocyte antigen (HLA) complex, particularly those encoding HLA-DR, have been suggested as markers of susceptibility to Kaposi’s sarcoma (KS). We conducted a case-control study comparing 147 homosexual men who developed KS after infection by human immunodeficiency virus-1 (HIV-1) and human herpes virus 8 (HHV8) with 147 matched dually infected men without HIV-associated KS (HIV-KS) from the Multicenter AIDS Cohort Study. HLA-B, DRB1, DRB3, DRB4, DRB5, and DQB1 polymorphisms were examined by high-resolution DNA-based methods. Differences in distributions of genetic variants were tested by conditional logistic regression. Previously reported relationships with HLA-DRB1 alleles could not be confirmed. Instead, other associations were observed. In univariate analysis, KS was weakly associated with B*2702/5 (odds ratio (OR)=0.40, 95% confidence interval (CI)=0.18-0.91). Similar or stronger associations, positive or negative, were seen for haplotypes containing class II alleles: DRB1*1302-DQB1*0604 (OR=3.67, 95% CI=1.02-13.1), DRB4 (DR53) haplotype family members [OR=0.52, 95% CI=0.32-0.85], and DRB3 (DR52) haplotype family members (OR=1.69, 95% CI=1.07-2.67). The B*1402-DRB1*0102 haplotype, which invariably contains the V281L mutation in the 21-hydroxylase gene governing adrenal steroid biosynthesis, occurred in five cases and one control (OR=5.0, 95% CI=0.58-42.8). In a final multivariable analysis, only DRB1*1302-DQB1*0604 (OR=6.43, 95% CI=1.28-32.3, P=0.02) remained significantly associated with KS. Associations of HLA-DRB families with HIV-KS could reflect underlying immune dysregulation. The HLA B*1402-DRB1*0102 haplotype associated with increased risk of KS might represent an antigen-presenting pathway unfavorable for immune response to HHV8.
– Having said all that, I still don’t really know what your point is. The study I cited in the previous post shows that low HHV8-specific T cell responses are a common factor in the development of both AIDS-related and non-AIDS classic Mediterranean KS. Based on that data, it seems reasonable to speculate that Thai people have more intact HHV8-specific T cell responses but until someone does a study in that population you can’t know for sure.
Dear Richard,
Thank you for your explaination of why kaposi Sarcoma is very rare 0.2% in Thailand with a high back ground of “hhv-8” and an “aids” epidemic. Its a most interesting answer and I thank you for taking the time to provide me with these possible theories/ unknown co/factors and references ect its very much appreciated.
As to the animal models that I am aware of one provided by Mr Christopher Nobel showing that a gene from “hhv-8” injected into mice induced Kaposi Sarcoma “like” lessions.
One that I found in pubmed.com from nature that showed that the “hiv” TAT gene injected into mice induced Kaposi Sarcoma “like” lessions but didnt contain “hhv-8”.
And one supplied By Eleni and The Perth Group that contained neither “hiv”, “hiv” TAT or “hhv-8” that induced Kaposi Sarcoma “like” tumours.
Whats your view , explaination , theories for these 3 different animal models containing different agents that induce Kaposi Sarcoma “like” lessions and Kaposi sarcoma like tumours please ?
Where is the evidence that “HIV” is causally related to KS? 25 August 2004
Christopher J Noble,
postdoc
Australia
“There is a bit more than just the correlation of HHV-8 with KS. There is temporal relation showing HHV-8 seroconversion before development of KS. There are also animal models for HHV-8 and KS. Etiology and pathogenesis of Kaposi’s sarcoma., Injection of human herpesvirus-8 in human skin engrafted on SCID mice induces Kaposi’s sarcoma-like lesions. ”
for a link to the one animal supplied by mr Christopher Nobel, thats the one that did contain “hhv-8” and induced KS “like” lessions please go here and click on Mr Nobels links.
http://groups.msn.com/AIDSMythExposed/general.msnw?action=get_message&mview=0&ID_Message=27986&LastModified=4675615045893464795
HHV-8 and KS 18 October 2004
Eleni Papadopulos-Eleopulos,
Biophysicist
Department of Medical Physics, Royal Perth Hospital, Western Australia, 6001,
Valendar F Turner, John Papadimitriou, Barry Page, David Causer, Helman Alfonso, Sam Mhlongo, Todd Miller, Christian Fiala
”
Christopher Noble gave us one paper which apparently he considers to contain “extremely strong evidence for the causal role of HHV-8 in Kaposi’s Sarcoma”. The paper by Nickoloff et al entitled: “Etiology and Pathogenesis of Kaposi’s Sarcoma” was published in Recent Results in Cancer Research, Vol. 160, page 331-342; 2002.
In his rapid response: “KS and UV”, 20 September, Nicholas Bennett wrote: “I have previously supplied information that supports the premise of HHV8 being an oncogenic virus epidemiologically associated with KS. The simplest conclusion (Occam’s Razor) being that it is the likely cause. Other factors do not share the same association. The Perth Group say that I have not done so, but I point them in the direction of the many responses here on the BMJ Rapid Responses, in particular one by myself dated 21st August. If the Perth Group choose to ignore them that is their perogative, but they cannot say I did not answer their request. They have clearly read it because it sparked the discussion regarding the carcinogenic properties of water and semen. It contains references that I’m sure will answer most or all of the questions regarding the oncogenicity of HHV8 and epidemiology of KS (if not them directly, then the references within).”
Epidemiological association is not proof for causation. Neither in Christopher Noble’s reference nor in any of Nicholas Bennett’s references is there any theoretical basis in respect of the claim that HHV-8 is carcinogenic. Nor is there any experimental evidence that HHV-8 is carcinogenic. All the researchers who have tried to induce KS by HHV-8 have reported that at best they could obtain, “cutaneous lesions resembling Kaposi’s sarcoma” or “Kaposi’s sarcoma-like lesions”. However, “dramatic depletion of CD4-positive cells, progressive impairment of the immune response, and Kaposi’s sarcoma-like tumours or terminal B- lymphomas”, can be induced “by mating BALB/c female mice to C57BL/6 males during 1-year period (7-10 allogenic pregnancies) followed by immunisation with paternal lymphocytes”.[1] ”
1. Ter-Grigorov VS, Krifuks O, Liubashevsky E, Nyska A, Trainin Z, Toder V. A new transmissible AIDS-like disease in mice induced by alloimmune stimuli. Nat Med 1997;3:37-41.
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Nature. 1988 Oct 13;335
The HIV tat gene induces dermal lesions resembling Kaposi’s sarcoma in transgenic mice.
Vogel J, Hinrichs SH, Reynolds RK, Luciw PA, Jay G.
Laboratory of Molecular Virology, National Cancer Institute, Bethesda, Maryland 20892.
When the human immunodeficiency virus transactivating gene under the control of the viral regulatory region is introduced into the germline of mice, skin lesions are induced that resemble Kaposi’s sarcoma seen in AIDS. Our findings indicate that HIV could play a direct part in causing cancer.
PMID: 2845275 [PubMed – indexed for MEDLINE]
Thank you
Best Wishes
James
Sorry, I have no idea what you’re asking. You seem to be implying that a mouse model of HHV8 & KS is required for you to accept causation but, frankly, I don’t see the world spinning off its axis if you prefer to believe that HHV8 doesn’t cause KS. Do you know what an antigen-specific T cell response is? Why do you think that a decline in HHV8-specific T cell responses is associated with the development of KS? Coincidence? Association doesn’t mean causation, of course, but the data have a certain amount of biological plausibility, no? Particularly given that the loss/dysfunction of T cell responses to many different pathogens is associated with the development of clinical disease.
Just to clarify, the lengthy quote I provided about HHV-8 in Thailand was not my “explanation,” it was taken directly from the paper about HHV-8 incidence that I thought you were citing but that you perhaps haven’t read:
Clin Infect Dis. 2004 Oct 1;39(7):1052-8. Epub 2004 Sep 13.
Seroprevalence of human herpesvirus 8 infection in Northern Thailand.
* Chen N,
* Nelson KE,
* Jenkins FJ,
* Suriyanon V,
* Duerr A,
* Costello C,
* Robison V,
* Jacobson LP.
Dear Richard,
perhaps you have not been following the debate here or the banned , censored debate in the BMJ.
Earlier on Mr Christopher Nobel used animal models to “prove” that “hiv” caused “aids”.
In the BMJ debate the same mouse model was toated as “the holly grail of cancer research” and proof positive that KS was caused by “hhv-8”
To quote again Mr Nobel from this debate using more or less exactley the same arguements he and his fellow believers used in the BMJ debate.
“#125Just to remind you, Mr Christopher Nobel stated:
“J,
Gallo and others knew a long time before 1994 that HIV was not the direct cause of KS. It was proposed fairly early that KS was caused by another sexually transmitted microbe by Valerie beral and others.
HHV-8 was subsequently discovered and its role in the pathogenesis of KS is firmly established with epidemoiolgy and animal models to support it.
HIV is believed to increase the risk of getting KS by a) immune suppression and b) HIV-tat activation of HHV-8.”
I replied:
http://groups.msn.com/AIDSMythExposed/general.msnw?action=get_message&mview=0&ID_Message=27986&LastModified=4675614897007893766
Please note there are 3 animal models of inducing KS “like” legions and 2 of them didnt contain “hhv-8”. The one that did contain “hhv-8” was supplied by Mr Noble during the banned BMJ debate.
Not only does the Thailand “hhv-8” seroprevence study show a high incidence of “hhv-8” more or less the same as gay/bi men in USA,West and Europe with a minute very rare incidence of KS 0.2% campared with 35%-55% KS incidence in gay/bi men in US, West and Europe, they also state “hhv-8” is not sexually transmited.
I will answer your other questions later when I return.
And I presume if one of the several theories put forward to explain the contradiction of Thailand having just 0.2% incidence of KS due to early childhood infection of “hhv-8” before “hiv” infection must mean that in Texas USA there must be also a minute 0.2% incidence of Kaposi Sarcoma if this one of the unevidenced theories put forward to explain this masive contradiction is correct.But some how I dont think in gay/bi men in Texas with “hiv” and “aids” the incidence of KS was any where near 0.2% more like 35%-55% despite high back ground rates 26% in School children under the of 12.
1: J Med Virol. 2002 Aug;67(4):542-8. Links
High prevalence of human herpesvirus 8 (HHV-8) infection in south Texas children.Baillargeon J, Leach CT, Deng JH, Gao SJ, Jenson HB.
Department of Pediatrics, The University of Texas Health Science Center, San Antonio 78284, USA. baillargeon@uthscsa.edu
Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus, is etiologically associated with Kaposi’s sarcoma and other rare malignancies. HHV-8 infection is common in certain areas of Africa and Italy, but occurs in only 0-15% of populations in North America and Europe. The epidemiology and prevalence of HHV-8 infection among children in the United States has not been determined, but is assumed to be low based on limited studies. The objective of this study was to determine the seroprevalence and possible risk factors of HHV-8 infection in children living in south Texas. Questionnaire data were collected and HHV-8 serologic tests were performed from a consecutive, non-probability sample of 123 healthy children (ages 4-13 years) attending general pediatric clinics in south Texas. Serum was tested for HHV-8 antibodies by latent immunofluorescence assay and ORF65 enzyme-linked immunosorbent assay confirmed by immunoblot. HHV-8 prevalence and 95 percent confidence intervals were calculated using standard epidemiologic methods. Logistic regression was used to assess independent risk factors associated with HHV-8 seropositivity. The overall prevalence of HHV-8 infection was 26%. No statistically significant associations were exhibited between HHV-8 prevalence and the variables under study. The prevalence of HHV-8 infection among children in south Texas, particularly among those under the age of 12 years, indicates that non-sexual transmission of this virus is likely to occur among this population. Future investigations of larger study samples will be necessary to develop an understanding of specific routes and risk factors of HHV-8 transmission among children in south Texas. Copyright 2002 Wiley-Liss, Inc.
PMID: 12116002 [PubMed – indexed for MEDLINE]
If your theory is correct that a sub section of “cd4″memory cells that recognise “hhv-8” and keep it in check are somehow lost more selectively in some populations but not others ,which moves the goal posts yet again is correct how do you explain the following. Now “orthadox” leaders and inventers of the “viral-load” predicts “cd4” and “cd4” predicts “aids” and Kaposi Sarcoma is called “aids” have finaly admittedd they where wrong which is the lynch pin of the “hiv=aids=death” theory.
It was and still is claimed by most researches that the reason KS get better when commencing “HAART” is because the “viral-load” goes down and as a result the “cd4” goes up and as a result of the “cd4” going up the mant diseases that can sometimes be called “aids” get better as a result of “cd4” going up. Which of course ignores the published evidence that shows “aids” diseases gettig better before “cd4” goes up or without “cd4” going up and “cd4” going up before the “viral-load” drops or even after “viral-resistance-rebound-increase”. references available.
http://www.thebody.com/catie/switch_ks.html
“At the time the PHAs were originally diagnosed with KS, all five had “widespread” skin tumours. They received chemotherapy and/or radiation therapy. Eventually they took PI-based combination therapy for about 2½ years, and their KS went into remission and cleared up. However, three of the PHAs’ therapy was eventually unable to suppress HIV levels; the remaining two wanted simpler regimens. So doctors changed their combinations to ones based on non-nukes instead of PIs.
After the Switch
On average, the KS relapsed one year after the PHAs switched from PIs to a non-nuke. At the time the relapse occurred, in four of the five PHAs, CD4+ cell counts were relatively high — ranging between 350 and 1,300 cells. Also, in four of the five PHAs, viral loads were low — fewer than 20 copies. ”
(added by jamesSo no immune suppression and above “normal” levels of “cd4” and virtualy “undetectable” “viral-load” so not much “hiv” TAT about either.)
“PIs and KS
The doctors note that the recurrence of KS in their patients cannot be explained by low CD4+ counts or high viral loads. In seeking other explanations, the doctors report certain results of test-tube and animal experiments done by researchers. In these experiments, PIs seem to prevent the growth and development of KS tumours. The drugs appear to do this by blocking the production of growth factors (chemical messengers) needed by KS cells. Moreover, exposure to PIs caused KS cells to die.
The report by the French doctors about KS relapse is interesting. However, much more study and analysis is needed to confirm these findings in other PHAs as well as to reconcile them with results from other clinical trials where combination therapy with either PIs or NNRTIs resulted in the regression of KS.”
and again I say the scientific evidence shows “hiv” P.I’s are NOT SPECIFIC to “hiv” as are all “arv’s” as claimed by “experts”
Oh by the way P.I. based “HAART” increases intracellular GSH and serum vit c and serum vit E and blocks /REDUCES apoptois/cell death induced by classic oxidizing agents that deplete GSH like AZT, radiation, morphine, hydrogen peroxide just like antioxidants do like NAC that also inhibits KS and reverses it in 50% of animals as well as approx doubling there life spans. Other succesfull “orthadox” KS treatments also modulate redox and increase GSH. Again references available.
Note Glycyrrhizic acid raises GSH. interesting also is that other antioxidants that inhibit “hhv-8” and kaposi Sarcoma like green tea extract also raise GSH. Alos interesting is that many immunosuppressive agents used in organ transplants are oxidizing and deplete GSH especially the ones used more frequentley in kidney transplants (and kidney dialysis is oxidizing as is kidney disease and KS cases occur in no immunesuppressed patients on kidney dialysis) which despite having lower rates of “hhv-8” compared to liver transplants have higher KS rates. Also interesting is KS breaking out in no immunesuppressed patients with hep “c” who have also been treated with GSH depleting drugs/hydrocortisone . Again loads of references available.
Thiol redox modulation of doxorubicin mediated cytotoxicity in cultured AIDS-related Kaposi’s sarcoma cells.
Mallery SR, Clark YM, Ness GM, Minshawi OM, Pei P, Hohl CM.
College of Dentistry, Department of Oral and Maxillofacial Surgery and Pathology, Ohio State University, Columbus 43210-1241, USA.
The chemotherapeutic, doxorubicin, is currently used empirically in the treatment of AIDS- related Kaposi’s sarcoma (AIDS-KS). Although often employed in a chemotherapeutic cocktail (doxorubicin, bleomycin, vincristine) single-agent therapy has recently been attempted with liposome encapsulated doxorubicin. Although doxorubicin’s mechanism of action against AIDS-KS is unknown, we hypothesized that doxorubicin’s ability to undergo redox cycling is associated with its clinical efficacy. The current study was conducted to investigate the effects of doxorubicin on selected xenobiotic-associated biochemical responses of three cellular populations: KS lesional cells, nonlesional cells from the KS donors, and fibroblasts obtained from HIV- aged matched men. Our results show that during doxorubicin challenge, there are strong positive correlations between cellular glutathione (GSH) levels and viability (r = 0.94), NADPH levels and viability (r = 0.93), and GSH and NADPH levels (r = 0.93), and demonstrate that as a consequence of their abilities to maintain cellular thiol redox pools HIV- donor cells are significantly less susceptible to doxorubicin’s cytotoxic effects relative to AIDS-KS cells. Additional studies further supported the contribution of reduced thiols in mediating doxorubicin tolerance. While pretreatment with the GSH precursor, N-acetylcysteine was cytoprotective for all cell groups during doxorubicin challenge, GSH depletion markedly enhanced doxorubicin’s cytotoxic effects. Studies to investigate the effects of a hydroxyl scavenger and iron chelator during doxorubicin challenge showed moderate cytoprotection in the AIDS-KS cells but deleterious effects in the HIV control cells. Inactivation of the longer lived membrane generated ROI in the cytoprotective deficient AIDS-KS cells, as well as an impairment of endogenous defenses in the HIV- donor control cells, may account for these scavenger and chelator associated findings. In summary, our findings show that doxorubicin mediates, at least in part, its AIDS-KS cellular cytotoxic effects by a redox related mechanism, and provides a biochemical rationale for doxorubicin’s clinical efficacy in AIDS-KS treatment.
Sent: 3/5/2005 10:13 AM
Courtesy Nicholas Bennett
J. Clin. Invest. 115:642-652 (2005). doi:10.1172/JCI200523334.
Copyright ©2005 by the American Society for Clinical Investigation
Glycyrrhizic acid alters Kaposi sarcoma-associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes
Francesca Curreli1, Alvin E. Friedman-Kien1,2 and Ornella Flore1,2
1Department of Microbiology and
2Department of Dermatology, New York University School of Medicine, New York, New York, USA.
Address correspondence to: Ornella Flore, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA. Phone: (212) 263-5313; Fax: (212) 263-7933; E-mail: ornella.flore@med.nyu.edu.
Received for publication September 13, 2004, and accepted in revised form December 21, 2004.
Kaposi sarcoma-associated herpesvirus (KSHV) is linked with all clinical forms of Kaposi sarcoma and several lymphoproliferative disorders. Like other herpesviruses, KSHV becomes latent in the infected cells, expressing only a few genes that are essential for the establishment and maintenance of its latency and for the survival of the infected cells. Inhibiting the expression of these latent genes should lead to eradication of herpesvirus infection. All currently available drugs are ineffective against latent infection. Here we show, for the first time to our knowledge, that latent infection with KSHV in B lymphocytes can be terminated by glycyrrhizic acid (GA), a triterpenoid compound earlier shown to inhibit the lytic replication of other herpesviruses. We demonstrate that GA disrupts latent KSHV infection by downregulating the expression of latency-associated nuclear antigen (LANA) and upregulating the expression of viral cyclin and selectively induces cell death of KSHV-infected cells. We show that reduced levels of LANA lead to p53 reactivation, an increase in ROS, and mitochondrial dysfunction, which result in G1 cell cycle arrest, DNA fragmentation, and oxidative stress-mediated apoptosis. Latent genes are involved in KSHV-induced oncogenesis, and strategies to interfere with their expression might prove useful for eradicating latent KSHV infection and have future therapeutic implications.
. Clin. Invest. 115:591-593 (2005). doi:10.1172/JCI200524507.
Copyright ©2005 by the American Society for Clinical Investigation
Correction sorry bad typing I missed a few N’s out should of read.
“and kidney dialysis is oxidizing as is kidney disease and KS cases occur in non immunesuppressed patients on kidney dialysis) which despite having lower rates of “hhv-8” compared to liver transplants have higher KS rates. Also interesting is KS breaking out in non immunesuppressed patients with hep “c” who have also been treated with GSH depleting drugs/hydrocortisone .”
Also please not unlike “viral-load” and “cd4” not predicting disease, “aids” or death intracellular glutathione GHS does. Again loads of references available.
“Walter Reed Army Institute of Research “…the presence of opportunistic infections is a criterion for the diagnosis of AIDS, but the presence of Kaposi’s sarcoma is omitted because the cancer is not caused by immune suppression…” (Redfield & Burke, 1988) “
You’re once again assuming an absolute correlation between low peripheral blood CD4 T cell counts and loss/dysfunction of particular antigen-specific CD4 T cell populations. The correlation is not absolute; low peripheral blood CD4 T cell counts are not a perfect marker of loss of Ag-specific CD4 T cells, they are a *surrogate marker* of disease progression (which in turn is caused by loss of Ag-specific immune function). This point is made repeatedly in the studies I posted, and it’s hardly surprising given that less than 2% of CD4 T cells are in the peripheral blood at any given time. There is nothing confounding about someone developing an opportunistic infection with a relatively high peripheral blood CD4 T cell count, but it is far more common for OIs to occur when the peripheral blood CD4 T cell count is low. This not moving any goal posts, this is what the immunology literature shows. Similarly, if you think the stuff about viral load and peripheral blood CD4 counts involves people “admitting they were wrong” then you haven’t understood the data I’m afraid.
In terms of your stuff about oxidation, HIV pathogenesis is driven by persistent immune activation and immune activation drives T cell activation and activation-induced cell death (apoptosis). These are normal events during any immune response, the difference in HIV infection is that the activation & apoptosis is persistent rather than transient. Trying to manipulate glutathione levels as a therapeutic strategy in this context is like trying to fix a broken car engine by putting more fuel in the tank; you’re not addressing the source of the problem. It’s the immune activation that leads to dysregulation of memory T cell pools, is this dysregulation which compromises the ability of the immune system to hold opportunistic pathogens in check. If it helps any, you can recapitulate this in mice by over-expressing the co-stimulatory molecule CD70; you get the same persistent activation and depletion of naive CD4 and CD8 T cell pools, along with dysregulation of memory T cells such that the mice get PCP.
All that HIV has to do to set up this chain of events is to compromise the immune response to itself; given that even Duesberg acknowledges that retroviruses need dividing cells, and given that the first dividing CD4 T cells that HIV encounters are HIV-specific CD4 T cells attempting to mount a response to it, surely it does not take a huge leap to see how this might happen. Indeed, HIV-specific CD4 T cells have been shown to be preferentially infected compared to cells of other specificities, and they have also been shown – consistently, in study after study – to be functionally compromised in all but long-term non-progressors. And since CD4 T cell help is required for the generation and maintenance of HIV-specific CD8 T cells and B cells, those responses are compromised, too.
Nat Immunol. 2003 Jan;4(1):49-54. Epub 2002 Dec 9.
Lethal T cell immunodeficiency induced by chronic costimulation via CD27-CD70 interactions.
Tesselaar K, Arens R, van Schijndel GM, Baars PA, van der Valk MA, Borst J, van Oers MH, van Lier RA.
Laboratory for Experimental Immunology, Academic Medical Center, P.O. Box 22700, 1100DD Amsterdam, The Netherlands.
It has been proposed that HIV-1, in addition to directly infecting and killing CD4+ T cells, causes T cell dysfunction and T cell loss by chronic immune activation. We analyzed the effects of chronic immune activation in mice that constitutively expressed CD70, the ligand for the tumor necrosis factor receptor family member CD27, on B cells. CD70 transgenic (CD70 Tg) mice showed a progressive conversion of naive T cells into effector-memory cells, which culminated in the depletion of naive T cells from lymph nodes and spleen. T cell changes depended on continuous CD27-CD70 interactions and T cell antigen receptor stimulation. Despite this hyperactive immune system, CD70 Tg mice died aged 6-8 months from Pneumocystis carinii infection, a hallmark of T cell immunodeficiency. Thus, persistent delivery of costimulatory signals via CD27-CD70 interactions, as may occur during chronic active viral infections, can exhaust the T cell pool and is sufficient to induce lethal immunodeficiency.
Nature. 2002 May 2;417(6884):95-8.
HIV preferentially infects HIV-specific CD4+ T cells.
Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, Casazza JP, Kuruppu J, Kunstman K, Wolinsky S, Grossman Z, Dybul M, Oxenius A, Price DA, Connors M, Koup RA.
Vaccine Research Center, NIAID, NIH, Maryland 20892, USA. ddouek@mail.nih.gov
HIV infection is associated with the progressive loss of CD4(+) T cells through their destruction or decreased production. A central, yet unresolved issue of HIV disease is the mechanism for this loss, and in particular whether HIV-specific CD4(+) T cells are preferentially affected. Here we show that HIV-specific memory CD4(+) T cells in infected individuals contain more HIV viral DNA than other memory CD4(+) T cells, at all stages of HIV disease. Additionally, following viral rebound during interruption of antiretroviral therapy, the frequency of HIV viral DNA in the HIV-specific pool of memory CD4(+) T cells increases to a greater extent than in memory CD4(+) T cells of other specificities. These findings show that HIV-specific CD4(+) T cells are preferentially infected by HIV in vivo. This provides a potential mechanism to explain the loss of HIV-specific CD4(+) T-cell responses, and consequently the loss of immunological control of HIV replication. Furthermore, the phenomenon of HIV specifically infecting the very cells that respond to it adds a cautionary note to the practice of structured therapy interruption.
J Immunol. 2006 Jun 1;176(11):6973-81.
Maintenance of HIV-specific CD4+ T cell help distinguishes HIV-2 from HIV-1 infection.
Duvall MG, Jaye A, Dong T, Brenchley JM, Alabi AS, Jeffries DJ, van der Sande M, Togun TO, McConkey SJ, Douek DC, McMichael AJ, Whittle HC, Koup RA, Rowland-Jones SL.
Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Unlike HIV-1-infected people, most HIV-2-infected subjects maintain a healthy CD4+ T cell count and a strong HIV-specific CD4+ T cell response. To define the cellular immunological correlates of good prognosis in HIV-2 infection, we conducted a cross-sectional study of HIV Gag-specific T cell function in HIV-1- and HIV-2-infected Gambians. Using cytokine flow cytometry and lymphoproliferation assays, we show that HIV-specific CD4+ T cells from HIV-2-infected individuals maintained proliferative capacity, were not terminally differentiated (CD57-), and more frequently produced IFN-gamma or IL-2 than CD4+ T cells from HIV-1-infected donors. Polyfunctional (IFN-gamma+/IL-2+) HIV-specific CD4+ T cells were found exclusively in HIV-2+ donors. The disparity in CD4+ T cell responses between asymptomatic HIV-1- and HIV-2-infected subjects was not associated with differences in the proliferative capacity of HIV-specific CD8+ T cells. This study demonstrates that HIV-2-infected donors have a well-preserved and functionally heterogeneous HIV-specific memory CD4+ T cell response that is associated with delayed disease progression in the majority of infected people.
J Virol. 2006 Oct;80(20):10162-72.
Infection of CD127+ (interleukin-7 receptor+) CD4+ cells and overexpression of CTLA-4 are linked to loss of antigen-specific CD4 T cells during primary human immunodeficiency virus type 1 infection.
Zaunders JJ, Ip S, Munier ML, Kaufmann DE, Suzuki K, Brereton C, Sasson SC, Seddiki N, Koelsch K, Landay A, Grey P, Finlayson R, Kaldor J, Rosenberg ES, Walker BD, Fazekas de St Groth B, Cooper DA, Kelleher AD.
Centre for Immunology, St. Vincent’s Hospital, Victoria Street, Darlinghurst, NSW 2010, Australia. j.zaunders@cfi.unsw.edu.au
We recently found that human immunodeficiency virus (HIV)-specific CD4+ T cells express coreceptor CCR5 and activation antigen CD38 during early primary HIV-1 infection (PHI) but then rapidly disappear from the circulation. This cell loss may be due to susceptibility to infection with HIV-1 but could also be due to inappropriate apoptosis, an expansion of T regulatory cells, trafficking out of the circulation, or dysfunction. We purified CD38+++CD4+ T cells from peripheral blood mononuclear cells, measured their level of HIV-1 DNA by PCR, and found that about 10% of this population was infected. However, a small subset of HIV-specific CD4+) T cells also expressed CD127, a marker of long-term memory cells. Purified CD127+CD4+ lymphocytes contained fivefold more copies of HIV-1 DNA per cell than did CD127-negative CD4+ cells, suggesting preferential infection of long-term memory cells. We observed no apoptosis of antigen-specific CD4+ T cells in vitro and only a small increase in CD45RO+CD25+CD127dimCD4+ T regulatory cells during PHI. However, 40% of CCR5+CD38+++ CD4+ T cells expressed gut-homing integrins, suggesting trafficking through gut-associated lymphoid tissue (GALT). Furthermore, 80% of HIV-specific CD4+ T cells expressed high levels of the negative regulator CTLA-4 in response to antigen stimulation in vitro, which was probably contributing to their inability to produce interleukin-2 and proliferate. Taken together, the loss of HIV-specific CD4+ T cells is associated with a combination of an infection of CCR5+ CD127+ memory CD4+ T cells, possibly in GALT, and a high expression of the inhibitory receptor CTLA-4.
Nature. 2006 Sep 21;443(7109):350-4. Epub 2006 Aug 20.
PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.
Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD.
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban 4013, South Africa.
Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.
AIDS Res Hum Retroviruses. 2006 Mar;22(3):272-82.
Defective IL-2 production by HIV-1-specific CD4 and CD8 T cells in an adolescent/young adult cohort.
Kapogiannis BG, Henderson SL, Nigam P, Sharma S, Chennareddi L, Herndon JG, Robinson HL, Amara RR.
Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30329, USA.
Here we investigate the effect of viremia and the influence of HAART on the frequency and quality of HIVspecfic T cells in an adolescent/young adult cohort. Measurements of viral loads and the magnitude and quality of antiviral cellular immune responses were performed on 14 HAART-naive and 8 treated HIV-1-infected adolescents. Cross-sectional correlations between viral load and cellular immune responses were determined and data were analyzed by viral load (less than 4000, 4000-40,000, and over 40,000 copies/ml plasma) and patient treatment status. All 22 patients showed a broad IFN-gamma ELISPOT response that was proportional to viral load (r = 0.53, p = 0.02), recognizing an average of five to eight peptide pools throughout Gag, Pol, Env, Tat, Rev, and Nef. Intracellular cytokine staining was performed with pools of overlapping peptides corresponding to HIV Gag to distinguish CD8 response from CD4 response. Among untreated patients with increased viral load there was a constant IFN-gamma CD8 response but a declining IFN-gamma CD4 response. HIV-specific IL-2 production was consistently low in CD8 cells but inversely related to viral load in CD4 cells (r = -0.52, p = 0.02). In this crosssectional analysis, time on HAART was associated with an increased frequency of antiviral IFN-gamma- and IL-2-coproducing CD4 cells (r = 0.98, p less than 0.001), but not of antiviral CD8 cells. Our results suggest that T cells coproducing IL-2 and IFN-gamma are a better marker for immunological competence than T cells producing IFN-gamma alone. They also suggest that HAART may be associated with an improved capacity for IL-2 production by antiviral CD4 T cells in a time-dependent manner. Longitudinal studies are clearly necessary to assess the impact of HAART on these parameters.
J Immunol. 2005 Dec 15;175(12):8415-23.
Functional and phenotypic characterization of CD57+CD4+ T cells and their association with HIV-1-induced T cell dysfunction.
Palmer BE, Blyveis N, Fontenot AP, Wilson CC.
Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
HIV-1 replication is associated with reduced or absent HIV-1-specific CD4+ T cell proliferation and skewing of HIV-1-specific CD4+ T cells toward an IFN-gamma-producing, CCR7- phenotype. The CCR7- T cell population is heterogeneous and can be subdivided based on the expression of CD57. Although CD57 expression on CD8+ T cells is associated with proliferation incompetence and replicative senescence, less is known about the function of CD57-expressing CD4+ T cells. In this study, the frequency, phenotype, and function of CD57+CD4+ T cells were evaluated in 25 HIV-1-infected subjects and 10 seronegative controls. CD57+CD4+ T cells were found to be proliferation incompetent, even after strong mitogen stimulation. Percentages of CD4+ T cells that expressed CD57 were significantly higher in untreated HIV-1-infected subjects than in HIV-1-seronegative donors, and CD57 expression did not normalize in subjects receiving at least 6 mo of effective antiretroviral therapy. CD57 was predominately expressed on the CCR7- fraction of the CD4+ T cell compartment and accounted for the majority of cells in the CCR7-CD45RA+ population from untreated HIV-1-infected subjects. HIV-1-specific CD4+ T cells producing only IFN-gamma had the highest expression of CD57, whereas few cells producing IL-2 alone expressed CD57. These findings further define a novel population of proliferation-incompetent CD4+ T cells that are generated in the presence of chronic Ag exposure. A better understanding of the generation and persistence of CD57+ T cells in HIV-1 infection could provide important insights into the immunopathogenesis of this disease.
J Virol. 2005 Nov;79(22):14169-78.
Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment.
Emu B, Sinclair E, Favre D, Moretto WJ, Hsue P, Hoh R, Martin JN, Nixon DF, McCune JM, Deeks SG.
Department of Medicine, San Francisco General Hospital, University of California, 94110, USA.
The human immunodeficiency virus (HIV)-mediated immune response may be beneficial or harmful, depending on the balance between expansion of HIV-specific T cells and the level of generalized immune activation. The current study utilizes multicolor cytokine flow cytometry to study HIV-specific T cells and T-cell activation in 179 chronically infected individuals at various stages of HIV disease, including those with low-level viremia in the absence of therapy (“controllers”), low-level drug-resistant viremia in the presence of therapy (partial controllers on antiretroviral therapy [PCAT]), and high-level viremia (“noncontrollers”). Compared to noncontrollers, controllers exhibited higher frequencies of HIV-specific interleukin-2-positive gamma interferon-positive (IL-2(+) IFN-gamma(+)) CD4(+) T cells. The presence of HIV-specific CD4(+) IL-2(+) T cells was associated with low levels of proliferating T cells within the less-differentiated T-cell subpopulations (defined by CD45RA, CCR7, CD27, and CD28). Despite prior history of progressive disease, PCAT patients exhibited many immunologic characteristics seen in controllers, including high frequencies of IL-2(+) IFN-gamma(+) CD4(+) T cells. Measures of immune activation were lower in all CD8(+) T-cell subsets in controllers and PCAT compared to noncontrollers. Thus, control of HIV replication is associated with high levels of HIV-specific IL-2(+) and IFN-gamma(+) CD4(+) T cells and low levels of T-cell activation. This immunologic state is one where the host responds to HIV by expanding but not exhausting HIV-specific T cells while maintaining a relatively quiescent immune system. Despite a history of advanced HIV disease, a subset of individuals with multidrug-resistant HIV exhibit an immunologic profile comparable to that of controllers, suggesting that functional immunity can be reconstituted with partially suppressive highly active antiretroviral therapy.
J Virol. 2004 Nov;78(22):12638-46.
Human immunodeficiency virus type 1 (HIV-1)-specific CD4+ T cells that proliferate in vitro detected in samples from most viremic subjects and inversely associated with plasma HIV-1 levels.
Boritz E, Palmer BE, Wilson CC.
University of Colorado Health Sciences Center, Campus Box B-164, 4200 East 9th Avenue, Denver, CO 80262, USA.
Diminished in vitro proliferation of human immunodeficiency virus type 1 (HIV-1)-specific CD4+T cells has been associated with HIV-1 viremia and declining CD4+ T-cell counts during chronic infection. To better understand this phenomenon, we examined whether HIV-1 Gag p24 antigen-induced CD4+ T-cell proliferation might recover in vitro in a group of subjects with chronic HIV-1 viremia and no history of antiretroviral therapy (ART). We found that depletion of CD8+ cells from peripheral blood mononuclear cells (PBMC) before antigen stimulation was associated with a 6.5-fold increase in the median p24-induced CD4+ T-cell proliferative response and a 57% increase in the number of subjects with positive responses. These p24-induced CD4+ T-cell proliferative responses from CD8-depleted PBMC were associated with expansion of the numbers of p24-specific, gamma interferon (IFN-gamma)-producing CD4+ T cells. Among the 20 viremic, treatment-naive subjects studied, the only 5 subjects lacking proliferation-competent, p24-specific CD4+ T-cell responses from CD8-depleted PBMC showed plasma HIV-1 RNA levels over 100,000 copies/ml. Furthermore, both the magnitude of p24-induced CD4+ T-cell proliferative responses from CD8-depleted PBMC and the frequency of p24-specific, IFN-gamma-producing CD4+ T cells expanded from CD8-depleted PBMC were associated inversely with plasma HIV-1 RNA levels. Therefore, proliferation-competent, HIV-1-specific CD4+ T cells that might help control HIV-1 disease may persist during chronic, progressive HIV-1 disease except at very high levels of in vivo HIV-1 replication.
J Immunol. 2004 Mar 1;172(5):3337-47.
Effects of sustained HIV-1 plasma viremia on HIV-1 Gag-specific CD4+ T cell maturation and function.
Palmer BE, Boritz E, Wilson CC.
Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
An in vitro proliferative defect has been observed in HIV-1-specific CD4(+) T cells from infected subjects with high-level plasma HIV-1 viremia. To determine the mechanism of this defect, HIV-1 Gag-specific CD4(+) T cells from treated and untreated HIV-1-infected subjects were analyzed for cytokine profile, proliferative capacity, and maturation state. Unexpectedly high frequencies of HIV-1-specific, IL-2-producing CD4(+) T cells were measured in subjects with low or undetectable plasma HIV-1 loads, regardless of treatment status, and IL-2 frequencies correlated inversely with viral loads. IL-2-producing CD4(+) T cells also primarily displayed a central memory (T(Cm); CCR7(+)CD45RA(-)) maturation phenotype, whereas IFN-gamma-producing cells were mostly effector memory (T(Em), CCR7(-)CD45RA(-)). Among Gag-specific, IFN-gamma-producing CD4(+) T cells, higher T(Em) frequencies and lower T(Cm) frequencies were observed in untreated, high viral load subjects than in subjects with low viral loads. The percentage of HIV-1 Gag-specific CD4(+) T(Cm) correlated inversely with HIV-1 viral load and directly with Gag-specific CD4(+) T cell proliferation, whereas the opposite relationships were observed for HIV-1-specific CD4(+) T(Em). These results suggest that HIV-1 viremia skews Gag-specific CD4(+) T cells away from an IL-2-producing T(Cm) phenotype and toward a poorly proliferating T(Em) phenotype, which may limit the effectiveness of the HIV-1-specific immune response.
J Exp Med. 2003 Dec 15;198(12):1909-22.
HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity.
Younes SA, Yassine-Diab B, Dumont AR, Boulassel MR, Grossman Z, Routy JP, Sekaly RP.
Departement de Microbiologie et Immunologie, Universite de Montreal, 2900 Edouard-Montpetit Boulevard, Montreal H3T 1J4, Canada.
CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester-based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA- CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA- CCR7- effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-gamma. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-gamma. Longitudinal analysis of HIV epitope-specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-gamma-producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2-producing CD4+ T cells and that IFN-gamma only-producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-gamma only-producing cells that lack self-renewal capacity.
J Immunol. 2003 Jun 1;170(11):5786-92.
HIV-1 replication increases HIV-specific CD4+ T cell frequencies but limits proliferative capacity in chronically infected children.
Scott ZA, Beaumier CM, Sharkey M, Stevenson M, Luzuriaga K.
Graduate Program in Immunology/Virology and Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01605, USA.
This study investigated the relationship between HIV-1 replication and virus (HIV-1; CMV)-specific CD4(+) T cell frequency and function in HIV-1-infected children. HIV-1 gag p55-specific CD4(+) T cell IFN-gamma responses were detected in the majority of children studied. p55-specific responses were detected less commonly and at lower frequencies in children with less than 50 copies/ml plasma HIV-1 RNA than in children with active HIV-1 replication. In children with less than 50 copies/ml plasma HIV-1, p55-specific responses were detected only in children with evidence of ongoing HIV-1 replication, indicating a direct relationship between HIV-1 replication and HIV-specific CD4(+) T cell frequencies. In contrast, p55-specific proliferative responses were detected more frequently in children with <50 copies/ml plasma HIV-1. CMV-specific CD4(+) responses were more commonly detected and at higher frequencies in CMV-coinfected children with suppressed HIV-1 replication. The lack of HIV-specific CD4(+) proliferative responses, along with the preservation of CMV-specific CD4(+) responses in children with controlled HIV-1 replication, suggests that viral replication may have deleterious effects on HIV-1 and other virus-specific CD4(+) responses. Vaccination to stimulate HIV-specific CD4(+) T cell responses in these children may synergize with antiretroviral therapy to improve the long-term control of viral replication, and may perhaps allow the eventual discontinuation of antiretroviral therapy.
J Immunol. 2002 Dec 1;169(11):6376-85.
Presence of HIV-1 Gag-specific IFN-gamma+IL-2+ and CD28+IL-2+ CD4 T cell responses is associated with nonprogression in HIV-1 infection.
Boaz MJ, Waters A, Murad S, Easterbrook PJ, Vyakarnam A.
Department of Immunology, Guy’s, King’s, and St. Thomas’ School of Medicine and Dentistry, King’s College London, United Kingdom.
HIV immunity is likely CD4 T cell dependent. HIV-specific CD4 T cell proliferative responses are reported to correlate inversely with virus load and directly with specific CD8 responses. However, the phenotype and cytokine profile of specific CD4 T cells that correlate with disease is unknown. We compared the number/function of Gag p24-specific CD4 T cells in 17 HIV-infected long-term nonprogressors (LTNPs) infected for a median of 14.6 years with those of 16 slow progressors (SPs), also HIV infected for a median of 14 years but whose CD4 count had declined to less than 500 cells/ micro l. Compared with SPs, LTNPs had higher numbers of specific CD4s that were double positive for IFN-gamma and IL-2 as well as CD28 and IL-2. However, CD4 T cells that produced IL-2 alone (IL-2(+)IFN-gamma(-)) or IFN-gamma alone (IFN-gamma(+)IL-2(-)) did not differ between LTNPs and SPs. The decrease in p24-specific CD28(+)IL-2(+) cells with a concomitant increase of p24-specific CD28(-)IL-2(+) cells occurred before those specific for a non-HIV Ag, CMV. p24-specific CD28(-)IL-2(+) cells were evident in LTNPs and SPs, whereas the CMV-specific CD28(-)IL-2(+) response was confined to SPs. The difference between LTNPs and SPs in the Gag p24 IFN-gamma(+)IL-2(+) response was maintained when responses to total Gag (p17 plus p24) were measured. The percentage and absolute number of Gag-specific IFN-gamma(+)IL-2(+) but not of IFN-gamma(+)IL-2(-) CD4s correlated inversely with virus load. The Gag-specific IFN-gamma(+)IL-2(+) CD4 response also correlated positively with the percentage of Gag-specific IFN-gamma(+) CD8 T cells in these subjects. Accumulation of specific CD28(-)IL-2(+) helpers and loss of IFN-gamma(+)IL-2(+) CD4 T cells may compromise specific CD8 responses and, in turn, immunity to HIV.
Blood. 2007 Feb 1; [Epub ahead of print]
PD-1 upregulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors, but not in long-term non-progressors.
Zhang JY, Zhang Z, Wang X, Fu JL, Yao J, Jiao Y, Chen L, Zhang H, Wei J, Jin L, Shi M, Gao GF, Wu H, Wang FS.
Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
The immunoreceptor PD-1 is significantly upregulated on exhausted CD8(+) T cells during chronic viral infections like HIV-1. However, it remains unknown whether PD-1 expression on CD8(+) T cells differs between typical progressors (TP) and long-term non-progressors (LTNP). In this report, we examined PD-1 expression on HIV-specific CD8(+) T cells from 63 adults with chronic HIV infection. We found that LTNP exhibited functional HIV-specific memory CD8(+) T cells with markedly lower PD-1 expression. TP, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 upregulation was also associated with reduced perforin and IFN-gamma production, as well as decreased HIV-specific effector memory CD8(+) T-cell proliferation in TP but not LTNP individuals. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8(+) T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 upregulation mediates HIV-specific CD8(+) T-cell exhaustion. Blocking PD-1/PD-L1 pathway may represent a new therapeutic option for this disease, and provide more insight into immune pathogenesis in LTNP individuals.
J Virol. 2007 Jan;81(1):434-8. Epub 2006 Oct 18.
Proliferative capacity of epitope-specific CD8 T-cell responses is inversely related to viral load in chronic human immunodeficiency virus type 1 infection.
Day CL, Kiepiela P, Leslie AJ, van der Stok M, Nair K, Ismail N, Honeyborne I, Crawford H, Coovadia HM, Goulder PJ, Walker BD, Klenerman P.
Nuffield Department of Medicine, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom.
The relationship between the function of human immunodeficiency virus (HIV)-specific CD8 T-cell responses and viral load has not been defined. In this study, we used a panel of major histocompatibility complex class I tetramers to examine responses to frequently targeted CD8 T-cell epitopes in a large cohort of antiretroviral-therapy-naive HIV type 1 clade C virus-infected persons in KwaZulu Natal, South Africa. In terms of effector functions of proliferation, cytokine production, and degranulation, only proliferation showed a significant correlation with viral load. This robust inverse relationship provides an important functional correlate of viral control relevant to both vaccine design and evaluation.
Blood. 2006 Jun 15;107(12):4781-9. Epub 2006 Feb 7.
HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells.
Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, Lederman MM, Benito JM, Goepfert PA, Connors M, Roederer M, Koup RA.
Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Establishing a CD8(+) T cell-mediated immune correlate of protection in HIV disease is crucial to the development of vaccines designed to generate cell-mediated immunity. Historically, neither the quantity nor breadth of the HIV-specific CD8(+) T-cell response has correlated conclusively with protection. Here, we assess the quality of the HIV-specific CD8(+) T-cell response by measuring 5 CD8(+) T-cell functions (degranulation, IFN-gamma, MIP-1beta, TNF-alpha, and IL-2) simultaneously in chronically HIV-infected individuals and elite nonprogressors. We find that the functional profile of HIV-specific CD8(+) T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8(+) T cells. This limited functionality is independent of HLA type and T-cell memory phenotype, is HIV-specific rather than generalized, and is not effectively restored by therapeutic intervention. Whereas the total HIV-specific CD8(+) T-cell frequency did not correlate with viral load, the frequency and proportion of the HIV-specific T-cell response with highest functionality inversely correlated with viral load in the progressors. Thus, rather than quantity or phenotype, the quality of the CD8(+) T-cell functional response serves as an immune correlate of HIV disease progression and a potential qualifying factor for evaluation of HIV vaccine efficacy.
Nat Med. 2006 Oct;12(10):1198-202. Epub 2006 Aug 20.
Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.
Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, Boulassel MR, Delwart E, Sepulveda H, Balderas RS, Routy JP, Haddad EK, Sekaly RP.
Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Universite de Montreal (CR-CHUM) Saint-Luc, 264 Rene Levesque Est, Montreal, Quebec H2X1P1, Canada.
The engagement of programmed death 1 (PD-1) to its ligands, PD-L1 and PD-L2, inhibits proliferation and cytokine production mediated by antibodies to CD3 (refs. 5,6,7). Blocking the PD-1-PD-L1 pathway in mice chronically infected with lymphocytic choriomeningitis virus restores the capacity of exhausted CD8(+) T cells to undergo proliferation, cytokine production and cytotoxic activity and, consequently, results in reduced viral load. During chronic HIV infection, HIV-specific CD8(+) T cells are functionally impaired, showing a reduced capacity to produce cytokines and effector molecules as well as an impaired capacity to proliferate. Here, we found that PD-1 was upregulated on HIV-specific CD8(+) T cells; PD-1 expression levels were significantly correlated both with viral load and with the reduced capacity for cytokine production and proliferation of HIV-specific CD8(+) T cells. Notably, cytomegalovirus (CMV)-specific CD8(+) T cells from the same donors did not upregulate PD-1 and maintained the production of high levels of cytokines. Blocking PD-1 engagement to its ligand (PD-L1) enhanced the capacity of HIV-specific CD8(+) T cells to survive and proliferate and led to an increased production of cytokines and cytotoxic molecules in response to cognate antigen. The accumulation of HIV-specific dysfunctional CD8(+) T cells in the infected host could prevent the renewal of a functionally competent HIV-specific CD8(+) repertoire.
Nat Immunol. 2002 Nov;3(11):1061-8. Epub 2002 Oct 7.
HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors.
Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, Hallahan CW, Van Baarle D, Kostense S, Miedema F, McLaughlin M, Ehler L, Metcalf J, Liu S, Connors M.
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
It is unclear why immunological control of HIV replication is incomplete in most infected individuals. We examined here the CD8+ T cell response to HIV-infected CD4+ T cells in rare patients with immunological control of HIV. Although high frequencies of HIV-specific CD8+ T cells were present in nonprogressors and progressors, only those of nonprogressors maintained a high proliferative capacity. This proliferation was coupled to increases in perforin expression. These results indicated that nonprogressors were differentiated by increased proliferative capacity of HIV-specific CD8+ T cells linked to enhanced effector function. In addition, the relative absence of these functions in progressors may represent a mechanism by which HIV avoids immunological control.
Dear Richard,
Please can you avoid being rude, insulting, and being arrogant as many people in your feild seem to think this type of behaviour is acceptable. Using words like lunacy, “denialist-denialism”, nonsense does not further anyones understanding or civil discussion or debate. Respect for an individual with a differing view is a signe of strengh not weakness. It may suite popular propaganda to slander, insult, misrepresent and dehumanise anyone who dares ask questions, or wants civil debate and free speech but it makes very bad science and manners. A few weeks back someone said I was a “holocaust denialists” because I questioned “hiv”, yet I do not deny that people are suffereing or that people have and are dying , but I do question the cause/s and I have a right to do so in a free world without being character assinated.
in reply to.
“For starters, let’s dispense with the “old diseases” nonsense please.”
Kaposi’s Sarcoma was first diagnosed in in 1872 with discriptions of it going back to ancient times , “pcp” was first in medical journals in malnurished children in the early 1920’s, cervicle cancer which was added on to the list of “aids” defining diseases in 1992 by the CDC has always existed, CMV has always existed, TB the number 1 “aids” defining diseases has existed as long as man has existed, as have all the diseases that can now sometimes be called “aids”. “hiv” may have been discovered in the early 1980’s but even Pro Luc Montaignier has said it could of been round for centuries. Reference available.
Now what is true is that there was a massive increase in some of these diseases starting of in the mid 1970’s and increasing dramiticaly through the early 1980’s but the massive increase of KS in the west was almost completeley restricted to gay and bi men only not other risk groups with “hiv”.
Prof Luc Montaignier who is the real discover of “hiv” who I disagree with on alot of things but also agree with on alot of things also has campaigned for the use of antioxidants, particulary glutathione boosting agents and has even written a huge book devoted to this fundamental issue of pathology in relation to redox and GSH. He also behaves like a gentleman and what I hope real scientists should behave like when confronted with questions, different views and civil debate.
Without civil debate ,questioning science will stagnate , standstill , be non progressive and without questioning we will never get answers. Once upon a time it was nonsense, lunacy to talk of evolution and books where burnt and poor Darwin under stress got skin disordersand was forced to leave london in fear for his safety such was the propaganda of hate and character assination that was developed and used against him. People once believed the world was flat and that it was lunacy to say it was round but we progressed and learnt. Your theory may be correct, it maybe half correct, it was not that long ago that it was the “holly bible” of “aids” “science” to say “hiv” RNA levels predicted cd4 and that cd4 predicted “aids” this year both these theories are in pieces, destroyed by non other than its originater Dr mellors and will be history soon and replaced by another theory ,hopefully a better predictive one with better understanding leading to better treatments as a result.
As for “hhv-8” I think it is related/associated to KS but that it is activation thats the problem and “hhv-8” is nothing more than a passanger virus at best and that it is not caused by immune suppression that I am certain of but its possible like you that I am wrong.
If you genuinely want to understand the discussion around the statistical assocations between viral load, peripheral blood CD4 T cell counts and disease progression try emailing Andrew Phillips in the UK. Among the conclusions from the studies that you seem to think have left people’s understanding of AIDS “in pieces” are these:
“a single CD4 count measurement had a much greater predictive value over short term periods: its predictive value was 76% over a time period of nine months”
“A single viral load measurement was only moderately predictive of the time to AIDS or death (23%) but a series of viral load tests was strongly predictive (61%).”
“Viral load and CD38 count together predicted 58% of the variability in time to AIDS, viral load and CD4 count 54% and CD4 and CD38 count 43%.”
http://aidsmap.com/en/news/D7725125-BC68-4D69-AF2F-D7EB1CCA746F.asp
CD38, of course, is a marker of immune activation and it’s expression is strongly and consistently associated with HIV RNA levels (rather undermining the repeated argument of AIDS denialists that viral load tests are meaningless – clearly, the immune system does not find them meaningless). If these analyses included other known predictors of disease progression – particularly HLA and chemokine/chemokine receptor genotypes – the predictive power would increase even further.
So, with apologies for my rather unfriendly writing style, I can only be honest and say that nothing you have written has altered my understanding of HIV infection and AIDS, which is primarily gleaned from the immunology literature. I always figured this was a reasonable approach to take, given that AIDS is an immunological disease.
Oh, and also you say “CMV has always existed” – this is dissembling. The point is “diseases” – is CMV retinitis really an “old disease”? Disseminated mycobacterim avium complex? Multiple opportunistic infections at once? Was this really happening a lot before HIV came along? The evidence is right there in PubMed, you can do the searches yourself. Peturbing the memory T cell pool as severely as HIV does can certainly enhance the ability of pathogens to cause diseases that they can also cause in the absence of HIV infection (TB, KS, HPV, etc.). But the compromise of T cell memory that occurs in HIV infection is so severe that it also allows pathogens that are normally controlled by the immune system (and therefore harmless) to cause disease that were hardly ever seen before. To try and pass these diseases off as somehow “normal” and “old” is just a lame propaganda tactic that aims to mislead the uninformed.
Dear Richard,
I am sure your a nice chap and I appreciate your answers and I respect you for at least trying to answer some of my many questions, I just dont think the word “denialist” should be applied to anyone who is questioning the cause/s of all the diseases that can sometimes be called “aids”. I have already stated that I agree with you and pubmed there was a huge explosion of unusuall diseases in the mid 1970’s and early 1980’s, I dont think anyone is “denying” that FACT. But some people including the man Peter Duesburge who was at the time one of the worlds leading retroviralologists, who was part of the team that first mapped out the genetic structure of retroviruses and was part of the team that discovered onco-genes (thought by many but not Peter to be the cause of some cancers) dont think “hiv” is the cause of “aids”, Peter who I have met and questioned at lengh and interviewed is a nice chap , I agree with him on some things but not others. Prof Luc Montaignier who I have met several times and the TV company I worked for have interviewed him several times and he has stated “hiv” alone is not the cause of “aids” but that there are cofactors involved , and he is absolutley of the opinion that oxidative stress and GSH defiency are of crital importance to cd4 loss, “hiv” PHA stimulation/culture/expression and disease progression .
http://www.altheal.org/treatments/oxidative.htm
“It has been found that AIDS is characterised by a persistent oxidative imbalance. An increasing deficiency of the non-toxic anti-oxidant glutathione plays a crucial role in the transition from pre-AIDS to full blown disease (1,2) To quote from Montagnier (the discoverer of HIV) et al (3):
Page 655:
“A large body of data on in vitro human immunodeficiency virus (HIV) infection and biochemical clinical studies suggests that oxidative stress plays a role in AIDS pathogenesis*. Recent reports have implicated intracellular excess of reactive oxygen species (ROS) in the induction of HIV expression (4-7) and in the initiation of apoptotic cell death ** (8). Studies showing a decrease in glutathione in peripheral blood mononuclear cells from symptom-free persons offer further evidence of a metabolic alteration leading to the decreased ability to counteract oxidative stress (9). These findings, together with other alterations of biochemical indicators of systemic oxidative damage that have been observed (10-12) suggest that antioxidants can be useful in inhibiting viral replication and cell death in patients with HIV infection and AIDS”
Page 662:
“It has been suggested that oxidative stress is a common mediator of apoptosis (8). This hypothesis stems from experimental evidence that oxidative stimuli induce apoptosis (13-15) while antioxidants inhibit it.”
“In AIDS pathogenesis oxidative stress is proposed as a metabolic alteration that favours disease progression by inducing both viral replication and apoptotic death”
Page 663:
“Indeed, evidence that oxidative stress induces, while antioxidants inhibit, HIV replication and apoptosis suggests the use of these molecules as an antiretroviral therapy to reduce cell death in AIDS patients”
In 1983 Luc Montagnier and in 1984 Robert Gallo stimulated cell cultures from tissues of AIDS patients with numerous oxidising (16) and mitogenic chemical agents and observed a number of phenomena which, long before the AIDS era, were known to be non-specific. By 1986 Montagnier and Gallo acknowledged that the “HIV” phenomena cannot be detected unless the cells are stimulated (17, 18). Subsequently researchers including Anthony Fauci, showed that when stimulated cell cultures are treated with reducing agents this greatly suppresses the appearance of such phenomena (4). >From the beginning of the AIDS era there has been evidence that individuals belonging to the AIDS risk groups are exposed to oxidising agents. In a 1998 study, researchers from Canada reported that supplementation of vitamin E and C reduces oxidative stress in “HIV” positives and produces a trend towards a reduction in “viral load”(19). I quote:
“This study is the first randomised controlled trial to demonstrate that, in an HIV-positive population, daily supplementation of 800 IU vitamin E and 1000 mg vitamin C significantly decreases oxidative stress and produces a trend towards a reduction in HIV viral load suggesting that there may be some clinical benefit worthy of larger clinical trials. Since combination antiretroviral therapies containing protease inhibitors are limited for economic reasons to only about 10% of HIV infected individuals in the world, consideration of the potential for this antioxidant therapy remains important for the developing world. It could have great benefit, perhaps similar to the effect of vitamin A supplementation on childhood mortality in developing countries.”
“Montagnier and his associate David Klatzmann were the first to draw attention to the fact that LAV infection of T4 cells in vitro does not lead to HIV expression unless the cells are stimulated. “Infection of resting T4 cells does not lead to viral replication or to expression of viral antigens on the cell surface, while stimulation by lectins or antigens of the same cells results in production of viral particles, antigenic expression and the cytopathic effect” (Klatzmann and Montagnier, 1986). Gallo also expressed the view that without “activation” the T4 cells do not express virus (Zagury et al., 1986). But, apparently, they did not realise that oxidative phenomena are implicated in human T-cell stimulation (Sekkat et al., 1988).” (69)
“Glutathione (GSH), a cysteine containing tripeptide is essential for the viability and function of virtually all cells. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV infected subjects. Specifically we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2 Ð 3 years after baseline data collection. This finding, supported by evidence that oral administration of the GSH prodrug N-acetyl cysteine and suggesting that N-acetylcysteine administration can improve their survival, establishes GSH deficiency as a key determinant of survival in HIV disease further it argues strongly that the unnecessary or excessive use of acetaminophen, alcohol or other drugs known to deplete GSH should be avoided in HIV infected individuals. (2)”
“Reduced plasma cysteine was significantly (p < 0.0001) lower in HIV-positive patients (13.0 +/- 3.0 ?M) when compared with control subjects (16.9 +/- 3.0 ?M). Although there was no difference in oxidized, protein-bound, and total cysteine, the thiol/disulfide ratios were lower in HIV-positive patients."(40) Also roughley one year after I helped research the above paper this study along with a huge editorial came out that showed a simple very primative (meaning I believe if they added NAC, selenium, ala, and other agents they would get much better results) very cheap 15 dolars a year vitamin pill reduced progression by 30%, sustained "cd4", reduced "viral-load" by 30% and could be used to delay alot more expensive and toxic "arv's". http://content.nejm.org/cgi/content/full/351/1/23?hits=20&where=fulltext&andorexactfulltext=and&searchterm=multivitamins+hiv&sortspec=Score+desc+PUBDATE_SORTDATE+desc&excludeflag=TWEEK_element&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
Volume 351:23-32 July 1, 2004 Number 1
Next
A Randomized Trial of Multivitamin Supplements and HIV Disease Progression and Mortality
Wafaie W. Fawzi, M.B., B.S., Dr.P.H., Gernard I. Msamanga, M.D., Sc.D., Donna Spiegelman, Sc.D., Ruilan Wei, Ph.D., Saidi Kapiga, M.D., Sc.D., Eduardo Villamor, M.D., Dr.P.H., Davis Mwakagile, M.D., M.Med., Ferdinand Mugusi, M.D., M.Med., Ellen Hertzmark, M.A., Max Essex, D.V.M., Ph.D., and David J. Hunter, M.B., B.S., Sc.D.
Editorial
by Marston, B.
ABSTRACT
Background Results from observational studies suggest that micronutrient status is a determinant of the progression of human immunodeficiency virus (HIV) disease.
Methods We enrolled 1078 pregnant women infected with HIV in a double-blind, placebo-controlled trial in Dar es Salaam, Tanzania, to examine the effects of daily supplements of vitamin A (preformed vitamin A and beta carotene), multivitamins (vitamins B, C, and E), or both on progression of HIV disease, using survival models. The median follow-up with respect to survival was 71 months (interquartile range, 46 to 80).
Results Of 271 women who received multivitamins, 67 had progression to World Health Organization (WHO) stage 4 disease or died — the primary outcome — as compared with 83 of 267 women who received placebo (24.7 percent vs. 31.1 percent; relative risk, 0.71; 95 percent confidence interval, 0.51 to 0.98; P=0.04). This regimen was also associated with reductions in the relative risk of death related to the acquired immunodeficiency syndrome (0.73; 95 percent confidence interval, 0.51 to 1.04; P=0.09), progression to WHO stage 4 (0.50; 95 percent confidence interval, 0.28 to 0.90; P=0.02), or progression to stage 3 or higher (0.72; 95 percent confidence interval, 0.58 to 0.90; P=0.003). Multivitamins also resulted in significantly higher CD4+ and CD8+ cell counts and significantly lower viral loads. The effects of receiving vitamin A alone were smaller and for the most part not significantly different from those produced by placebo. Adding vitamin A to the multivitamin regimen reduced the benefit with regard to some of the end points examined.
Conclusions Multivitamin supplements delay the progression of HIV disease and provide an effective, low-cost means of delaying the initiation of antiretroviral therapy in HIV-infected women.
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Heres what Gus Cairns wrote formere editor of very “orthadox” http://www.positivenation.uk about Dr Mellors latest turn around.
“The rate at which an untreated HIV-positive person’s CD4 cell count is declining is a poor predictor of the risk of AIDS or death in individual patients the Fourteenth Conference on Retroviruses and Opportunistic Infections was told this week… medium-term baseline CD4 decline was a very poor predictor: it only predicted 2.9% of the time to AIDS… This means that medium term CD4 decline – the quantity Rodriguez said was poorly predicted by viral load – is itself a useless predictor of progression to AIDS…” — Cairns, Gus, 2007. “CROI: Rate of CD4 decline is a poor guide to the risk of AIDS, say investigators”, 2 March 2007, aidsmap news.”
Why not quote the Gus Cairns article in full, then? I was quoting from the same piece (follow the link). The phrase “medium term” is rather important. You’re so desperate to justify your own flawed understanding of the disease that you’re clutching at oxidated straws. What’s the cite that showed glutathione deficiency in T cells from people with HIV? Did they run the same assay and show that in vivo administration of NAC to people with HIV corrected the glutathione deficiency in their CD4 T cells? Or might you perhaps need to consider that glutathione deficiency is an effect of CD4 T cell dysfunction rather than a cause and that the cause is upstream (impaired differentiation due to cell cycle arrest, for example).
The effect of multivitamins on mortality in the study you’re citing appears to be zero – the confidence interval crosses 1 and the p value is non-significant (p=0.09).
http://mednews.stanford.edu/releases/1997/febreleases/HerzHIV.html
“The more of these molecules patients carry in their CD4 T cells (the primary cells targeted by the HIV virus), the longer the patients are likely to survive, report Leonore and Leonard Herzenberg, genetics professors at the Stanford University School of Medicine.
The molecule, called glutathione, plays a role in many of the body’s normal activities, ranging from cell division to mopping up oxidants and other toxic molecules.
“It’s been known since 1989 that people with HIV have CD4 cells deficient in glutathione. Now we know that glutathione levels matter to patients’ survival,” said Leonard Herzenberg, who will present the new finding Saturday, Feb. 22, at the annual meeting of the American Association of Immunologists, in San Francisco.
The Herzenbergs’ finding could help doctors treat HIV disease more effectively, perhaps by preventing further loss of glutathione or by boosting its levels in patients who need more of it, he said.
The finding also raises the possibility that drugs such as the common painkiller acetaminophen (sold under the brand name Tylenol and others) are hazardous to people with HIV or with other conditions that suppress immune function, added Leonore Herzenberg.
“What we show for the first time in this work is that people with HIV who have lower glutathione levels have a much lower probability of surviving over the course of three years than do people with normal glutathione levels,” Leonard Herzenberg said.
The study also demonstrates that glutathione levels can be used with CD4 counts for a more reliable indicator of the progression of HIV disease, according to the researchers.
Clinicians today commonly track the progression of HIV disease by measuring the total number of CD4 cells in a blood sample; patients with low counts are considered at risk of earlier death due to HIV. “But total CD4 counts don’t reliably predict how long an individual patient is likely to live or how rapidly the person’s disease will progress. Some patients with low CD4 counts unexpectedly survive for a very long time,” Leonore Herzenberg said.
The Herzenbergs, a well-known husband-and-wife research team at Stanford, worked with study coordinator Greg Dubs; genetics research fellows Dr. Stephen De Rosa, Mario Roederer, Michael Anderson and Stephen Ela; and clinical assistant professor of medicine Dr. Stanley Deresinski. A full report of their findings will appear in the March 4 issue of the journal Proceedings of the National Academy of Sciences, the Herzenbergs said.
A total of 204 patients took part in the study. When the patients joined the study, all of them were HIV positive but had no outward signs of illness. Over the next three years, the researchers found that patients who maintained normal glutathione levels — even if their CD4 counts were low — tended to outlive those with low glutathione levels.
The study included 99 patients with CD4 counts below 200 cells per microliter of blood — the threshold clinicians view as an imminent threat to survival. Most patients who had such low levels of CD4 cells and also had low levels of glutathione died within three years.
“In contrast, of the 28 people who started the study with low CD4 counts but maintained normal glutathione levels, 23 survived. In other words, about 80 percent of these people survived, even though their CD4 cell counts indicated their survival was unlikely,” Leonard Herzenberg said.
The researchers stress the importance of maintaining adequate levels of glutathione for HIV patients.
One potential way to do this, they suggest, is to give HIV patients a drug called N-acetylcysteine (NAC), which is normally used to treat acetaminophen overdose. Their study showed that daily NAC tablets were able to boost the glutathione in patients’ blood to a healthy level.
The study also raises concerns about acetaminophen use by people with HIV. “Our findings lead us to ask two questions: Is it safe for people with HIV to take acetaminophen and other drugs that deplete their stores of glutathione? And should all HIV patients take a drug like NAC that will help to maintain their glutathione levels?” Leonard Herzenberg said. ”
Also please note that cocaine increases dramiticaly “hiv” expression, creates cortisol which causes cd4 migration (as you correctley stated only 2% of cd4 rests in the the blood) and cortisol depletes glutathione, crystal meths also increases “hiv” expression, causes wasting and massively decreases cd4 and is a potent oxidiser and depletes GSH and also induces neuro cell death/apoptosis, poppers used by gay men have also been shown to reduce glutathione, and nac and glutathione as I refrenced earlier may be of benefit in treating and preventing TB, selenium defiency in IV drug users predicts a 17 fold increase in TB which can be defined as “aids” and is Africa’s number 1 “aids” defining disease.
We shouldnt just be looking at CD4 and “viral-load” there are other major important factors and in my view GSH levels are more important than cd4 and “viral-load” in terms of survival.
When “arv’s” are used antioxidants can be used along side and they increase the positive effects and decrease the side effects.
The recent case of the “supervirus” in new york was nothing to do with the none existant “supervirus” and everything to do with the fact the man was a heavy crystal meths addict.
I suggest you take that up with Editor of the New England Journal of Medicine who wrote a huge editorial on the peace, also wasting predicts disease and death better than cd4.
if your suggesting that morphine, radiation, azt, hydrogen peroxide dont induce cell death apoptosis in “infected” and non “infected” cells and that antioxidants dont block /reduce cell death apoptosis as do P.I’s then your are sadley mistaken and I can give you over 1000 references from the best journals in world , but still you can scoff all you like your just displaying your ignorance on the subject.
So, glutathione supplementation restores CD4 T cell function to normal levels then? Ag-specific proliferation, Ag-specific IL-2 production, etc.? I’d be interested in seeing that data. It doesn’t seem to be in what you’ve posted here.
The fact is that people with very very low cd4’s -50 can inhibit KS for very long periods of time and they can remain disease free.
cd4’s are not the b all and end all of life, sometimes diseases like malaria, TB, stress, drug addiction, malnutrition, protein defiencies, selenium defiencies, glutamine defiences predict and cause diseases, when UV hits the lense it destroys GSH and helps with the formation of cataracts, if you inject cortisol into chick embryo’s they develope cataracts, if you give them antioxidants they get far less cataracts, NAC reverses KS tumours in 50% of animals and doubles there life span, Alpha lipoic acid which raises GSH reduces cell death from radiation and helps prevent DNA damage and mitochondrial damage.
Simply search pubmed for nac KS or nac aids, or nac hiv, or search google for glutathione nac TB, selenium TB, or do some neuro research and find out how antioxidants reduce cell death from crystal meths like acetyl l carnitine and NAC, or search pubmed for peripherial neurapathy caused by “ARV’s” and chemo and radiation and see how acetyl l carnitine, NAC, ALA all help prevent and reverse peripherial neuropathy induced by oxidizing agents that deplete glutathione like cytotoxic dna chain terminator AZT.
try searching iv l carnitine in peole with previousley declining cd4’s with “hiv” and hep “c” and see how the cd4 goes up 100 to 150% plus with NO CHANGE in “viral-load” or even an increase in “viral-load” all in pubmed.com
Strange how I had two friends in two weeks at the same clinnic in London with “pcp” on “successfull” “arv” with “undetectable” “viral-loads” and 700+ cd4 and one can hardley walk due to nerve damage left untreated caused by “arv” when they know full well antioxidants like acetyl l carnitine can reverse and reduce pain , but who cares just stick them on pain killers dont treat the mitochondrial dna atp damage , then give them more drugs to treat the side effects of the pain killers.
http://content.nejm.org/cgi/content/full/351/1/23?hits=20&where=fulltext&andorexactfulltext=and&searchterm=multivitamins+hiv&sortspec=Score+desc+PUBDATE_SORTDATE+desc&excludeflag=TWEEK_element&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
From The New England Journal of Medicine.2004
“In addition to enhancing immunity, multivitamins may also reduce HIV replication, as indicated by the significant reduction in viral load. HIV replication in vitro is increased by oxidative stress.27 Components of our multivitamin supplement, particularly vitamins C and E, are potent antioxidants. In a small, randomized, placebo-controlled study of 49 HIV-positive patients, those who received daily supplements of both vitamin E (800 IU) and vitamin C (1000 mg) for three months had a significant reduction in lipid peroxidation (a measure of oxidative stress), with a trend toward a reduced viral load.28
The benefits with respect to immunologic and virologic outcomes in our study were small relative to the effects of triple antiretroviral therapy. However, the effects of multivitamins on the CD4+ cell counts and viral load were similar to, and in some cases larger than, those of early trials, which compared therapy with a single antiretroviral agent with placebo or dual therapy with single-drug treatment, as well as recent trials comparing three-drug therapy with two-drug therapy.29 In a meta-analysis of studies that evaluated treatment-mediated changes in CD4+ cell counts and viral load as surrogates for the progression of HIV disease (progression to AIDS or death), the relationships between these markers and the risk of progression were linear.30 Applying our observed reduction of 0.18 log in the viral load to this linear relation results in an increase in the time to progression to AIDS or death of approximately 30 percent, similar to the size of the effect that we observed. ”
Note reference 27 which follows, simply all in vitro studies absolutley require pha stimulation/oxidation to obtain “hiv” expression without oxidation/stimulation you dont get expression of “hiv” add antioxidants and you reduce/block “hiv” expression same applies to apoptosis /cell death.Just as Prof Luc Montaignier has repeatedly stated and he is the real discover of “hiv” and unlike the other “discover” of “hiv” Dr Robert Gallo he doesnt run away and pull funny faces on live TV (CNN) when you ask him a scientific question.
EMBO J. 1991 Aug;10(8):2247-58. Related Articles, Links
Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1.
Schreck R, Rieber P, Baeuerle PA.
Laboratorium fur Molekulare Biologie, Ludwig-Maximilians-Universitat Munchen, FRG.
Hydrogen peroxide and oxygen radicals are agents commonly produced during inflammatory processes. In this study, we show that micromolar concentrations of H2O2 can induce the expression and replication of HIV-1 in a human T cell line. The effect is mediated by the NF-kappa B transcription factor which is potently and rapidly activated by an H2O2 treatment of cells from its inactive cytoplasmic form. N-acetyl-L-cysteine (NAC), a well characterized antioxidant which counteracts the effects of reactive oxygen intermediates (ROI) in living cells, prevented the activation of NF-kappa B by H2O2. NAC and other thiol compounds also blocked the activation of NF-kappa B by cycloheximide, double-stranded RNA, calcium ionophore, TNF-alpha, active phorbol ester, interleukin-1, lipopolysaccharide and lectin. This suggests that diverse agents thought to activate NF-kappa B by distinct intracellular pathways might all act through a common mechanism involving the synthesis of ROI. ROI appear to serve as messengers mediating directly or indirectly the release of the inhibitory subunit I kappa B from NF-kappa B.
Correction . Selenium defiency in iv drug users predicts a 13 fold increase in TB not 17 fold. And yes Richard you are right to say that apoptosis can cause oxidative stress, but oxidative stress can drive apoptosis, also infections like TB, EBV, CMV, malaria, malnutrian can cause lowering of cd4 and oxidative stress and drive apoptosis , so when you treat the infecions or defiencies the cd4 can go up either through reducing apoptosis or through TH1./TH2 to balance to shift to th2 dominance and glutathione has been shown to shift th2 dominance back to Th1 dominance or to govern/modulate th1/th2 balance or combinations of both or throught the echanism proposed by Eleni and the perth group. Selenium by the way is involved in GSH production modulation. cd4 can be the effect of variouse diseases , defiencies and not always the cause. For instance UV radiation activates “hiv”, herpes, cmv and lots of other viruses it also is oxidising and depletes GSH.
http://www.altheal.org/treatments/oxidative.htm
“”Malnutrition, and selenium levels of 135 g/L (patients with these levels were 13 times more likely to develop mycobacterial disease). (32)
“Multivariate analyses controlling for antiretroviral treatment and CD4 cell count revealed that both body mass index and selenium level remained significant factors in the relative risk for developing mycobacterial disease (relative risk, 3; p = .015); these findings suggest that selenium status may have a profound impact on the pathogenesis of mycobacterial disease.”(32)
“These results indicate that selenium deficiency is an independent predictor of survival for those with HIV-1 infection.”(34)
“Over the course of the study, 12 children died of HIV-related causes. The final Cox multivariate analysis indicated that, of the variables evaluated, only CD4 cell count below 200 (risk ratio [RR] = 7.05; 95% confidence interval [CI], 1.87-26.5); p = .004], and low levels of plasma selenium (RR = 5.96; 95% CI, 1.32-26.81; p = .02) were significantly and independently related to mortality.”(35)
“Among the children who died, those with low selenium levels (85 g/L), died at a younger age, suggesting more rapid disease progression “Conclusions: In pediatric HIV-infection, low plasma level of selenium is an independent predictor of mortality, and appears to be associated with faster disease progression.”(35)
Last year however, Carbonari et al showed that apoptotic (apoptosis = programmed cell death) lymphocytes in AIDS patients consist for the most part of CD8 T-cells and CD19 B-cells.(1) They concluded from this that the phenomenon of in-vitro apoptosis might not be related to the depletion of CD4 T-cells in AIDS. Finkel et al recently showed that apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes.(2) In their commentary, Pantaleo and Fauci did not wish to give any conclusive answer to this.(3) (44)
Montagnier: “Being able to reduce apoptosis to a normal rate in lymphocytes of HIV-infected individuals would put HIV infection in a class with mononucleosis and other chronic infections where cell death does occur, but the immune system goes back to normal after a period of time. In the middle and later stages of HIV infection, apoptosis is a chronic and permanent problem. Antioxidants including NAC might slow the rate of apoptosis. Apoptosis is not limited to HIV infection, but proceeds at a higher rate in HIV-infected cells.” (27)
“Other cofactors may be some ordinary proteins or some external factors which are present before infection or even carried along with the HIV, and oxidative stress. If we act on the causative agents that lead to increased apoptosis — free radicals, microbial factors, viruses — or interact with the many steps of the apoptosis process, we can reduce cell death to a normal rate.”(27)
“We should treat oxidative stress at the earliest possibility. This requires measuring the oxidative stress markers in the blood and tailoring the treatment to the individual based on the results of these tests.” (27)
Montagnier: “I strongly believe that one important factor is the activation of the T-helper cells. Consecutive T-cell receptor stimulation induces T-cell deletion by apoptosis. [4] Recognizing the importance of apoptosis in AIDS progression may have dramatic implications for developing new treatments for AIDS. Apoptosis may induce oxidative stress. We know also that oxidative stress can mediate apoptosis. This is a circular cascade.”(27)
“We sought evidence that azathioprine causes cell death through reduced glutathione (GSH) depletion and mitochondrial injury.” (73) The mechanism of azathioprine toxicity to hepatocytes involves depletion of GSH leading to mitochondrial injury with profound depletion of ATP and cell death by necrosis. Cell death was prevented by potent antioxidants, glycine and blocking the mitochondrial permeability transition pore.” . (73). “To investigate the role of decreased GSH content in the toxicity of thiram, GSH levels were modulated prior to exposure. Pretreatment of fibroblasts with N-acetyl–cysteine (NAC), a GSH biosynthesis precursor, prevented both lipid peroxidation and cell death induced by thiram exposure. In contrast, thiram cytotoxicity was exacerbated by the previous depletion of cellular GSH by -buthionine-(S,R)-sulfoximine (BSO). Taken together, these results strongly suggest that thiram induces GSH depletion, leading to oxidative stress and finally cell death.” (74)
“The mechanism for nucleoside analogue -related PN is thought to be impaired neuronal mitochondrial DNA synthesis and repair which disrupts energy metabolism causing die-back of long peripheral axons. L-acetyl carnitine is an amino acid that enhances retrograde neurotrophic support of sensory neurons, and which suffers a decrease in serum levels in HIV neuropathy.
This open observational cohort study by Mike Youle performed lower leg skin biopsies on four patients with established PN (Grade 2-4) before and after 6 months oral LAC treatment (1500mg BID). Frozen sections were immunostained using fibre-type specific primary antibodies (PGP, GCRP, VIP) and FITC-labelled secondary sera, and were examined by fluorescence microscopy and optimized by digital photography. All sections were stained and analyzed at the same time. The system used for computerized image analysis for each of three skin areas (epidermis, dermis and ecrine sweat glands) has already been validated for use in diabetes-related neuropathy.
Results showed an increase in area of immunostaining of 40% (p=0.22) for all fibre types and 493% (p=0.002) for small sensory fibres. The study noted a trend towards greater percentage increases with increased duration of neuropathy. In sweat glands the mean increase was 293% (p<0.001) for all nerve fibres and 273% (p<0.001) for sympathetic efferents.
All patients reported an improvement in symptoms and three of these four patients had continued nucleoside treatment throughout the study. Clinical grade of dysaesthetic pain improved from grade 3-4 at baseline to grade 1-2 following treatment with LAC. [11] .”(39)
“A study of antioxidant rescue in mice treated with NRTI’s was presented by Jay Lenhard from Glaxo Wellcome, Research Triangle Park, NC, USA [5]. In this mice were treated with placebo or NRTI’s for 2 weeks with or without concomitant anti-oxidants, ascorbate and alpha-tocopherol. Whilst the presence of the NRTI’s clearly induced metabolic changes and damage to the oxidative phopshorylation pathway of energy production within the mitochondria, the presence of the antioxidants produced a marked 70% reduction in this damage. (39)”. http://www.i-base.info/pub/htb/vol1/htb2/htb2.html#L-Acetyl
“Peripheral neuropathy (numbness/tingling/burning in the feet and sometimes, hands) occurs in up to one-third of persons with HIV infection. Any one of three NRTI (nucleoside reverse transcriptase inhibitor) drugs also can cause the condition. Those are the so-called “d drugs,” including ddC (Hivid, zalcitabine), ddI (Videx, didanosine) and d4T (Zerit, stavudine). Peripheral neuropathy also is caused by diabetes, the antibiotics dapsone and isoniazid (INH), vitamin B12 deficiency, chronic alcoholism, leprosy and those who have had cancer chemotherapy with vincristine. In HIV, peripheral neuropathy is associated with toxicity to “mitochondria,” (energy producing component of cells) which may be caused to varying degrees by drugs within the NRTI class.” “Michael Youle, MD, from the Royal Free Center for HIV Medicine in London, UK, presented the results of a small observational study with the conclusion that oral L-acetyl carnitine improved symptoms of peripheral neuropathy. Also, those improvements correlated with increased nerve tissue staining from biopsies in four patients.” (39)
AZT depletes the anti cancer molacule reduced glutathione (GSH) as shown above it damages mitondrial DNA, There are already thousands of people who have died of cancers related to AZT but doctors are in “denial” about the increased incidence of these cancers caused by monotherapy AZT. P.I’s amd 3tc and its relatives REDUCE apoptosis, mitondrial DNA damage by oxidising agents like AZT.
http://www.sciencedaily.com/releases/2007/04/070406140932.htm
Drug Used To Prevent HIV Transmission From Mother To Child Damages DNA
Science Daily — Studies demonstrate that AZT causes genetic damage that may increase future cancer risk.
“However, previous research has shown that NRTIs also incorporate into the DNA of host cells, causing damage that could have long-term health consequences for those exposed to the drugs.
Two new animal studies have examined the cancer-causing effects of transplacental exposure to AZT in mice and rats and found increased rates of tumors and tumors with gene changes that frequently occur in human cancer. In addition, two human studies are the first to observe the induction of mutations and large scale chromosomal damage in red blood cells of newborns exposed to NRTIs in utero. ”
“These, and other, studies were published in April 2007 in a special issue of Environmental and Molecular Mutagenesis that examines the latest research on DNA damage and potential health risks related to the use of NRTIs. Besides the effects of NRTIs on nuclear DNA and cancer risk, the issue also contains recent findings on the toxicity of these drugs toward mitochondrial DNA.
Researchers led by Dale M. Walker of Experimental Pathology Laboratories in Herndon, VA, administered AZT in varying doses to female mice and rats during the last 7 days of gestation and examined the tissue of their offspring two years later. They found clear evidence of an AZT-induced increase in the incidence of hemangiosarcoma (cancer originating in cells that line the blood vessels) in male mice and mononuclear cell leukemia in female rats.
There was also some evidence of increased liver cancer and reproductive tumors. “Although the implications of these findings for the long-term health of human children exposed tranplacentally to AZT are uncertain, the possibility of increased cancer risk for a subset of these children in mid and late adulthood appears highly plausible,” the authors state.
The carcinogenic effects of AZT were further demonstrated by a study on mice led by Hue-Hua Hong of the National Institute of Environmental Health Sciences in Research Triangle Park, NC. This study found mutations in the K-ras and p53 cancer genes that are often mutated in human lung tumors. The development of lung cancer in these mice suggests that the incorporation of AZT or its metabolites into DNA, oxidative stress, and genomic instability may be the contributing factors to the pattern of mutations observed in the study, according to the authors. They conclude, “The cumulative mutagenesis data suggest that infants exposed transplacentally to AZT may be at increased risk for cancer as they age.”
In the first of the two human studies, researchers led by Patricia A. Escobar of the University of Pittsburgh, in Pittsburgh, PA, measured DNA damage caused by AZT in the blood of newborns. They found increased frequencies of glycophorin A mutations in the red blood cells of newborns who had been exposed to AZT plus lamivudine (another type of NRTI) in utero, and these changes persisted for the most part through one year of age. The researchers note that although the combination of the two NRTIs is more effective at preventing transmission of HIV from mother to fetus, it is also more genotoxic than AZT alone. They conclude that “there is a need for careful monitoring of the future health of children who received peripartum AZT-based therapies, the development of new safer NRTIs, and the identification of antimutagenic drugs that will mitigate the side effects of NRTI-based highly active antiretroviral therapy.”
In the second study involving humans, researchers led by Kristine L. Witt of the National Institute of Environmental Health Sciences in Research Triangle Park, NC measured the frequency of immature red blood cells (reticulocytes; RET) containing micronuclei (MN), indicators of chromosomal damage, in blood samples of HIV-infected women and their infants exposed to antiretroviral drugs during pregnancy. Most, but not all, of the prenatal treatment regimens in this study included AZT. At birth, the researchers observed ten-fold increases in the frequencies of micronucleated reticulocytes (MN-RET) in the women and infants whose prenatal drug regimen included AZT. ”
Please note there is SIGNIFICANT evidence showing that antioxidants NAC, reduced glutathione, acetyl l caritine, vit e, vit c, ala can reduce mitochondrial damage by agents like AZT that deplete anti cancer molacule reduced glutathione (GSH) no wonder I saw so many friends waste away on AZT, watched there KS explode and get worse and worse, watched them die with dementia and “pcp” to do with low levels of GSH in lungs and pro GSH agents inhibit TB, KS,”pcp”, wasting,candida albicans, and drugs that oxidise and deplete GSH induce candida albicans, KS, wasting, nerve damage , mitochondrial DNA damage while antioxidants inhibit these effects including cell death.
Lung Cancer ROS Glutathione smoking Advise sought
From: GlutathioneSurvival1 Sent: 6/27/2006 1:04 AM
http://www.positivenation.co.uk/issue123/treatment/treatment3/treatment3.htm
Lung cancer risk higher in HIV positive
People living with HIV appear to be at greater risk of getting lung cancer, even if they are non-smokers, research suggests. And the extent of a person’s immune system damage seems to have no bearing on the risk.
Researchers analysed 5,238 HIV positive people attending Baltimore clinics between 1989 and 2003. Lung cancer rates in this group were compared to a group of HIV negative people.
Thirty-three lung cancers occurred in the study group. Being older was identified as a risk factor for lung cancer, but gender, race, and CD4 cell count appeared to have no effect. Almost 70 per cent of the people with HIV in the cohort smoked. But even non-smokers in the group were still more likely to develop lung cancer than HIV negative people.
“As people with HIV live longer, lung cancer will likely grow in importance as a cause of morbidity and mortality,” the authors concluded.
“Clinicians should be alert to the possible diagnosis of lung cancer in HIV-infected patients,” they added.
Sent: 9/18/2004 9:03 PM
Toxicol Appl Pharmacol. 1988 Nov;96(2):324-35. Related Articles, Links
Glutathione metabolism and utilization of external thiols by cigarette smoke-challenged, isolated rat and rabbit lungs.
Joshi UM, Kodavanti PR, Mehendale HM.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
The purpose of the present investigation was to understand the acute effects of cigarette smoke on glutathione (GSH) metabolism and on utilization of external thiols by cigarette smoke-exposed, perfused rat and rabbit lungs. Most of the experiments were carried out using freshly drawn cigarette smoke. However, cigarette smoke condensate was used in some perfusions for the comparison of the effects between the types of exposures on utilization of external thiols. Cigarette smoke decreased GSH levels significantly (50%) without any increase in glutathione disulfide (GSSG) in both rabbit and rat lungs. In smoke-exposed rabbit lungs, protein thiol groups (protein-SH) decreased significantly (17%) without a significant change in protein-GSH mixed disulfides. However, in the rat lungs, cigarette smoke did not decrease protein-SH and protein-GSH mixed disulfides, indicating species variation in the effect of cigarette smoke. Cigarette smoke inhibited selenium-dependent and -independent GSH peroxidase activities in the rat lung (33%), but not in the rabbit lung. GSH S-transferase and GSSG reductase activities were not altered in cigarette smoke-challenged rabbit and rat lungs. gamma-Glutamylcysteine synthetase and glucose-6-phosphate dehydrogenase activities were significantly lower in smoke-exposed rat lungs as against control lungs, indicating that rat lung enzymes were more susceptible to the effects of cigarette smoke when compared to those of rabbits. N-Acetylcysteine, but not GSH, added to the perfusate significantly protected rabbit lung from smoke-induced GSH depletion. Smoke condensate added to the perfusate also caused GSH depletion in rabbit lung, and GSH or N-acetylcysteine added to the perfusion medium protected the lung indicating that GSH in the media directly interacts with condensate in the media before coming in contact with cellular GSH. These results indicate that acute smoke inhalation decreases pulmonary GSH and that the decreased GSH was not related to disulfide formation. Inhibited GSH synthesis in rat lung could account for the loss of GSH in part after exposure to cigarette smoke. The alternative pathway of GSH utilization could be conjugation with electrophilic smoke components. Thiols, like N-acetylcysteine, were protective against cigarette smoke-induced damage to the rabbit lung. The mechanism could be either by the increased GSH synthesis or by the direct delivery of sulfhydryls from N-acetylcysteine
For full paper go here
http://cebp.aacrjournals.org/cgi/content/full/11/2/167
N-Acetyl-L-cysteine (NAC) has been shown to exert cancer-protective mechanisms and effects in experimental models. We report here the results of a randomized, double-blind, placebo-controlled, Phase II chemoprevention trial with NAC in healthy smoking volunteers. The subjects were supplemented daily with 2 x 600 mg of oral tablets of NAC (n = 20) or placebo (n = 21) for a period of 6 months, and internal dose markers [plasma and bronchoalveolar lavage (BAL) fluid cotinine, urine mutagenicity], biologically effective dose markers [smoking-related DNA adducts and hemoglobin (Hb) adducts], and biological response markers (micronuclei frequency and antioxidants scavenging capacity) were assessed at both pre- and postsupplementation times (T0 and T1, respectively). Overall, the internal dose markers remained unchanged at T1 as compared with T0 in both NAC and placebo groups. When quantifying the biologically effective dose markers, we observed an inhibitory effect of NAC toward the formation of lipophilic-DNA adducts (5.18 ± 0.73 versus 4.08 ± 1.03/108 nucleotides; mean ± SE; P = 0.05) as well as of 7,8-dihydro-8-oxo-2′-deoxyguanosine adducts in BAL cells (3.9 ± 0.6 versus 2.3 ± 0.2/105 nucleotides; P = 0.003). There was no effect of NAC on the formation of lipophilic-DNA adducts in peripheral blood lymphocytes or polycyclic aromatic hydrocarbon-DNA adducts in mouth floor/buccal mucosa cells or 4-aminobiphenyl-Hb adducts. Likewise, quantification of the biological response markers showed an inhibitory effect of NAC on the frequency of micronuclei in mouth floor and in soft palate cells (1.3 ± 0.2 versus 0.9 ± 0.2; P = 0.001) and a stimulating effect of NAC on plasma antioxidant scavenging capacity (393 ± 14 versus 473 ± 19 µM Trolox; P = 0.1) but not on BAL fluid antioxidant scavenging capacity. We conclude that NAC has the potential to impact upon tobacco smoke carcinogenicity in humans because it can modulate certain cancer-associated biomarkers in specific organs.
Sent: 9/28/2004 3:45 PM
Protective effects of anethole dithiolethione against oxidative stress-induced cytotoxicity in human Jurkat T cells.
Author: S Khanna, CK Sen, S Roy, MO Christen, and L Packer
Source: Biochem Pharmacol 1998;56(1): 61-9 UI:98361555
Abstract: The protective effects of anethole dithiolethione (ADT) against H2O2- or 4-hydroxynonenal (HNE)-induced cytotoxicity in human Jurkat T cells were investigated. Jurkat T cells were pretreated with ADT (10-50 microM) for 18 hr and then challenged with H202 or HNE for up to 4 hr. Cytotoxicity was assessed by measuring: 1) leakage of lactate dehydrogenase from cells to medium; and 2) exclusion of the DNA intercalating fluorescent probe propidium iodide by viable cells. Pretreatment of cells with ADT (10 or 25 microM) for 18 hr significantly protected cells against H202- or HNE-induced cytotoxicity. Treatment of cells with ADT (10-50 microM) for 72 hr significantly increased the activities of catalase and glutathione reductase. The maximum effect of ADT treatment on the activity of these enzymes was observed when cells were treated with 25 microM of ADT for 72 hr. A significant increase in cellular GSH was observed in cells that were treated with ADT for 72 hr. Using monobromobimane as a thiol probe, we consistently observed that cells pretreated for 18 hr with ADT (25 or 50 microM) had also increased total thiol content. Exposure of Jurkat T cells to H202 or HNE resulted in a time-dependent decrease in cellular GSH. ADT (10-50 microM, 18 hr) pretreatment circumvented H202-dependent lowering of cellular GSH. In conclusion, ADT proved to be a potent cytoprotective thiol antioxidant with multifaceted mechanisms of action, suggesting that the drug has a remarkable therapeutic potential.
Publication Type: Journal article
Title Abbreviation: Biochem Pharmacol
Year: 1998
Address: Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.
© 2004 Oxford University Press (unless otherwise stated)
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http://www.altheal.org/treatments/oxidative.htm
“Reduced apoptosis is associated to cancer development. Agents able to restore the programmed cell death responsiveness of cancer cells are foreseen as potential effective cancer therapies. In this study, we report that a glutathione-S-derivative, S-acetyl-glutathione (Sag), induces significant apoptosis in three human lymphoma cell lines,including Daudi, Raji and Jurkat cells while it had no or little effect on either Hut-78 lymphoma cells or the normal B lymphocytes.”(59)
for full paper with graphs about SAG go here
http://147.52.72.117/IJO/2002/volume20/number1/69-75.pdf
Journal of Clinical Oncology 2006; 24: 1383-1388
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
http://groups.msn.com/AIDSMythExposed/healthissues.msnw?action=get_message&mview=0&ID_Message=11945&LastModified=4675612130144121656&all_topics=0
-GSH= -survival -protection+ drug side effects
jamesjwhiteheadUK (Original Message) Sent: 1/15/2005 8:49 AM
http://groups.msn.com/AIDSMythExposed/healthissues.msnw?action=get_message&ID_Message=10091&ShowDelete=0&ID_CLast=10258&CDir=-1&all_topics=0
Lung Cancer ROS Glutathione smoking Advise sought
jamesjwhiteheadUK (Original Message) Sent: 9/5/2004 3:38 PM
Research roundup
Old drug offers new hope for lung cancer prevention
John Macfarlane
A drug developed to treat dry mouths may also prevent smokers from succumbing to lung cancer. Lung tumours are the biggest cause of cancer-related death and account for over 150,000 deaths every year in the United States alone.
It is well established that smoking is the primary cause of lung cancer and, although giving up will greatly reduce the risk of developing the disease, ex-smokers — especially those who have smoked for a long period — still carry a residual risk. One in two people who are treated for lung cancer are ex-smokers, and ex-smokers have a 15% risk of developing the disease during their lifetime.
This week, Stephen Lam from the British Columbia Cancer Agency told the annual meeting of the American Association for Cancer Research in San Francisco that anethole dithiolethione (ADT) — which is marketed as Sialor by the French company Solvay Pharmaceuticals — may be an effective cancer chemopreventative agent.
Lam reported the results of phase II clinical trials of ADT in 101 Canadians who had smoked a packet of cigarettes a day for over 30 years and showed pre-cancerous signs in the form of bronchial dysplasia. Two-thirds of the subjects still smoked, but a third had managed to quit.
The drug was administered orally for six months and its effects were compared against a cohort who took a placebo. No serious side-effects — aside from potentially embarrassing flatulence — were reported. The group receiving ADT showed 22% less progression and proliferation of displasic lesions than those who received the placebo.
It is thought that ADT exerts its protective effect by upregulating the expression of glutathione S-transferase, an enzyme that is known to have anti-oxidatative effects and to be responsible for breaking down some carcinogens.
Commenting on this study, Frank Rauscher, Editor-in-Chief of the journal Cancer Research, said that the important thing about ADT was that it had already passed through clinical trials, had been found to be non-toxic and was approved for use in Europe and Canada (but not by the US Food and Drug Administration). He said the results “warranted immediate follow-up” in large-scale phase III trials.
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After adjustment for age, race, smoking status, and gender, HIV-infected men in HOPS faced a 2.13-fold increased risk of lung cancer (95% CI: 1.06, 4.27), a 4.6-fold increased risk of Hodgkin’s disease (95%CI: 3.10, 6.77), a 10.1-fold increased risk of anorectal cancer (James I wonder why and which risk group comes of worst for this type of cancer?) (95% CI: 7.48, 13.72), and a 2.99-fold increased risk of melanoma (95% CI: 1.71, 5.22), compared with what was expected based on SEER data, the study showed. Among HIV-infected patients in the Chicago area, similar increases were observed relative to the general population, Dr. Patel said.
+
Some studies have found higher-than-normal levels of cigarette usage
in HIV positive people. Since HAART has had an impact on some HIV-related
complications, researchers are interested in understanding the impact of
HAART on lung cancer. To do this, researchers in London, England,reviewed
information in their database of 8,400 PHAs.
Results In analysing data between 1986 and 2001, the researchers
found the following: 11 HIV positive people (one female, 10 males)
were diagnosed with lung cancer, all of whom were tobacco smokers.
Nine of the 11 developed lung cancer in the time HAART was available (1996
-2001). Six of the nine were taking HAART at the time cancer was
diagnosed. The other three had sufficiently high CD4+ cell counts and
did not require HAART at the time their cancers developed.
The response of the tumours to anti-cancer therapy (radiation or
chemotherapy) was not good, and half of the subjects did not survive
beyond five months after their cancer diagnosis.”
“The researchers found that in the time before HAART, the risk of
developing lung cancer was about the same in HIV negative and HIV positive
people. However, in the years since HAART has become available, the risk
of developing lung cancer in HIV positive people has become about eight times greater than that in HIV negative people. ” (57b)
“Between 2000 and 2002, the most common cause of death at the UK’s
largest HIV clinic, London’s Kobler Centre, was cancer: non-hodgkin’s
lymphoma (NHL) and non-AIDS-defining cancers(such as lung ,testicular and
anal cancer.(57b)
Cancer in Scotland: swings and roundabouts
Scottish scientists, from universities of Strathclyde and Glasgow and the
Scottish Cancer Registry, were surprised, last month, to find the risk of
non-Aids defining cancers (such as lung, skin and liver cancer) up to 22
times higher in HIV positive people. Homosexual men topped the list as the
group most likely to develop cancers of any kind. The UK’s first dedicated
male-only cancer centre opened in Edinburgh last week – hailed as an
example of innovation and reform which “puts the patient’s needs at the
heart of the health service.”
http://groups.msn.com/aidsmythexposed/general.msnw?action=get_message&mview=0&ID_Message=9971&LastModified
=4675487326421030223
An editing mechanism inhibitors such as GSH & GSTT1+/- glutathione S-transferases and PAH to human subjects suppressed by a neighboring silencer element operative when expression of Pcp-2 (termed, pancreatic carcinoma phosphatase-2) becomes hormone-independent, formation and Ca2+/K+ spiking subunits of the V gene-encoded regions are also unable to perform V(D)J.
This article can be found on the I-SIS website at
http://www.i-sis.org.uk/
========================================================
“Let Us Live and Let Them Die”
*****************************
A WHO staff member’s parting salvo to the international
health agency and its neoliberal approach to health.
Sam Burcher
———————————————————
A fully referenced version of this article is posted on ISIS
members’ website.
An electronic version of this report, or any other ISIS
report, with full references, can be sent to you via e-mail
for a donation of £3.50. Please e-mail the title of the
report to: report@i-sis.org.uk
Alternatively, order you copy of ISIS Report Unraveling AIDS
and get a free CD of all new articles and others on AIDS
from SiS archives to bring you right up to date
http://www.i-sis.org.uk/onlinestore/books.php#236
———————————————————-
Social scientist, Alison Katz has left the World Health
Organisation (WHO) after 17 years of devoted service,
condemning its “Let us live and let them die” attitude,
which sums up the neglect of millions of people over the
past three decades, suffering and dying from diseases of
poverty, including notably HIV/AIDS [1]. She is the second
AIDS researcher to leave within the past 12 months (see On
Quitting HIV [2] this series).
“For over twenty years now, the international AIDS community
has persisted in a reductionist obsession with individual
behaviour and an implicit acceptance of a deeply flawed and
essentially racist theory.” Katz writes. She believes that
the narrow and totalitarian approach to AIDS by the WHO not
only has had negligible effect, but also has betrayed public
health principles and perversely forbidden exploration of
any alternative perspectives. Like many others, Katz
questions the exclusion of a plethora of co-factors known to
increase biological susceptibility to infection by all
disease agents, including HIV, among which are under-
nutrition, poverty, powerlessness, and the basic necessities
for a healthy and dignified life.
She believes that the WHO has fallen victim to neoliberal
globalisation, and by default, to the economic interests of
powerful nations and the transnational corporations. In an
open letter dated January 2007 [3] addressed to Dr. Margaret
Chan, the incoming Director-General of WHO, Katz set out
seven key points to steer her focus back to serving the
public, including the critical importance of addressing the
commercialisation of science, and the close relationship
between industry and academia as highlighted in ISIS’
Discussion Paper Towards a Convention on Knowledge [4].
The neoliberal approach to health
———————————
There is a strong tendency in the neoliberal approach to
health – and particularly in relation to HIV/AIDS, to blame
victims, Katz says [5], for their faulty or irresponsible
behaviour. Demeaning stereotypes, coupled with flawed
analysis, and ineffectual policies do not appear to have
contributed to any significant decrease in infection rates
in the worst affected regions such as the continent of
Africa. Furthermore, the world’s first global sex survey
published in The Lancet in 2006 found that multiple sex
partners were more common in industrialized countries where
disease incidence is relatively low [6]. According to Katz,
the dominant neoliberal perspective reinforces the
structures of hegemony that create poverty and powerlessness
which are themselves the root causes of avoidable disease
and death. (Poverty eradication must be central to change
and the narrow focus to the problem is being challenged by
women in Africa (see Women Confront Aids in Africa SIS 34
[7]).
Eileen Stillwaggon, an associate Professor of Economics at
Gettysburg College USA, says that [8] the ecology of poverty
must be understood, as populations that lack access to
medical care and are already coping with parasitic and
multiple other infections, are more vulnerable to other
diseases, regardless of how they are transmitted. In this
respect, HIV/AIDS is no exception. The public health
principle, neatly summarized by Pasteur as “the bacteria is
nothing; the terrain is all”, applies to all the diseases of
poverty. The focus on individual sexual behaviour is itself
highly stigmatising – in addition to being unscientific. On
an optimistic note, Stillwaggon observes that solutions to
the problems caused by almost all the co-factors exist, and
institutions, like the WHO are well placed to advocate for
them among vulnerable populations. ISIS has proposed many
affordable and patent-free alternative treatments to the
disease and its’ co-factors in Unraveling AIDS [9]).
In order to neutralise the entrenched neoliberal bias within
international agencies Katz believes that the WHO must
return to its founding principles and advocate for attention
to root causes – the social and economic determinants of
health and disease. In today’s world, this implies
denouncing unfair rules of trade and commerce, the
exploitation of national resources, and ruthless
liberalization foisted on developing countries, all of which
have been shown to have devastating effects on the health of
populations. Furthermore, the WHO must take the lead in
providing scientific research with independent scientists
free of vested interests. To achieve its mandate of “Health
For All”, the WHO must support serious science based on
sound evidence. Millions of people’s lives are at stake.
Political prejudice within the WHO
———————————-
Katz worked for 12 years in the division of WHO dealing with
family, community, sexual and reproductive health, and 8
years in the HIV/AIDS department. In 1999 she responded to
an Internet discussion posting from the perspective of
biological vulnerability to HIV infection and racist
assumptions underlying current policies and strategies. Her
supervisor, on instructions from the executive director,
immediately censored her by sending an email instructing
that she must not debate this issue. At the same time she
received a request from the editor of the African Journal of
Aids Research to write up her ideas in an article [1].
Shortly after that, she was isolated from all technical work
within her department for 18 months.
Following her isolation, Katz’s contract was not renewed, so
she submitted an internal legal appeal against the WHO for
reinstatement and for a proper contract after serving 11
years on 37 temporary contracts. She won the appeal on
condition that she leave the HIV/AIDS department. As a
working mum supporting three children, she had no choice but
to accept the Director General’s offer.
Efforts on Katz’s part to discuss alternative approaches
with the WHO HIV/AIDS programme director and the UNAIDS
executive director have consistently been declined, even
after the publication of the Lancet series, mentioned above,
which supports the perspective she is advocating.
Independence of international civil servants to fulfil WHO’s
mandate
————————————————————
Katz’s concerns expanded to the question of independence of
international civil servants, which is seriously undermined
by neoliberal influence exerted through powerful member
states, private sources and extra-budgetary funding.
Pressures at this level have resulted in a repressive,
authoritarian and hierarchical management style, which
discourages free debate. Katz joined the staff association
to fight for proper contracts for all long term “temporary
staff” – some 55 percent of the workforce. The success of
this action was limited. A very small proportion of “false
temps” were regularized into proper contracts and then
through a major, costly “restructuring” exercise, many of
these long serving staff then lost their jobs, often to
inappropriately qualified appointees with better
connections.
These struggles took place against what she describes as a
background of nepotism, cronyism, corruption, harassment,
financial mismanagement and chaotic, highly discretionary,
human resources management [5]. Furthermore there is an
under representation of Africans, Asians, Latin Americans,
or Eastern Europeans within staff departments. The
predominant influence of the UK, USA and Canada, as well as
Australia, and New Zealand; whose representatives are
invariably white, male, Anglo-Saxon Protestants linked by
powerful networks prevails.
WHO’s first strike and out
————————–
Together with a small group in the staff association, Katz
organized a one hour work stoppage, the first industrial
action in WHO’s history, in which 700 staff participated.
Her post was abolished three weeks after the work stoppage
and three weeks before the normal renewal of her 2-year
contract. Swiss unions and staff association lawyers qualify
this as interference in the right of association; the WHO
administration qualifies it as a “coincidence”.
Katz believes that the WHO must respect international labour
standards, including negotiation status for the staff
association, in line with ILO (International Labour
Organisation) covenants; to provide workers with formal
power, adequate funding, and strong links to a bona fide UN
umbrella union. WHO staff should be held accountable to
WHO’s 1978 constitutional mandate, to the Alma Ata
principles underlying Health for All, and to the UN Charter
and should fully understand the duties and responsibilities
of public service.
WHO’s challenge to achieve Health for All
—————————————–
Katz calls for a return to a basic needs and rights-based
approach to health [1] in order to provide a sustainable and
meaningful response to AIDS that is simultaneously a
response to all the diseases of poverty. An alternative
political strategy for AIDS and its co-factors would embrace
macroeconomic reforms for a fair, rational and sustainable
international economic order so that democratically elected
governments may reasonably meet people’s basic needs,
including health, without external interference.
In her open letter [3], Katz urges WHO’s newly elected
Director General, Dr Chan, to address the following major
issues in order to fulfil her vision. A focus on inequality
rather than poverty; holding meetings and consulting with
the poor rather then the rich; a solid, equitable tax base,
nationally and internationally, rather than public-private
partnerships; knowledge for the public good rather than
corporate “science”; respect for ethical values and an
appropriate balance between loyalty to WHO’s constitutional
mandate and loyalty to current governments of powerful
member states and current office holders.
Read the rest of this article here
http://www.i-sis.org.uk/LULALTD.php
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the suboptimal context of the codon GSH.
While I’d love to read the scientific literature and evaluate the claims and counter claims for myself, I find most of it is behind a pay wall. ie. It’s back to “Poor and doomed to remain Ignorant man, Trust me, I’m a Doctor”.
So if people really believe reading the literature is the solution to the debate, then they should also believe that PLoS is one of the most important projects of the decade.
Incidently, my favourite PLoS paper is the charming
Why Most Published Research Findings Are False
and, John Carter (an ER character??) wins the award for:
Best attempt at resurrection
do you want to borrow Kathy Griffin’s acceptance speech, or did you already have one prepared?
ER character
WTF? Google suggests you may be talking about American tv.. I wouldn’t know. Don’t have time for TV and even if I did it wouldn’t be American.
Interesting comments, these three.
Let’s face it, no one who is not a dissident is going to read links to an HIV dissident site, especially when some of the papers are by Duesberg. People may read papers from mainstream scientists so long as they support their own arguments. Everyone here is interested in furthering their own arguments. Period.
Posted by: wayne | March 19, 2007 7:46 PM
“Not only have I read Duesberg’s articles but I have checked his claims with the ‘orthodox’ literature. It is only after this that I concluded that duesberg is full of crap.”
And therefore everyone reading this blog should take Chris Noble’s word for it. Just like everyone takes nature’s and Science’s “word for it” when they also say Duesberg is full of crap. My guess is that (unlike Chris Noble) 99% of people who take [fill in the blank]’s “word for it” have not actually taken time to examine the “dissident literature” (or even the “orthodox literature” which dissidents allegedly “cherry-pick” and “abuse”). My guess is, 99% of people who dismiss dissidents out of hand do so simply because “everyone else thinks so…”
And then everyone wonders why it’s NOT impossible for such a blunder to have happened…
Jake
Posted by: Jake | March 24, 2007 6:51 AM
DT said: “I dismiss dissidents because I have taken the trouble to look in detail at their claims, and found them wanting”.
DT, as with most of what you have to say, that statement of yours is not true at all!
DT dismisses the HIV dissidents because DT is a HIV drug rep to doctors for a pharmaceutical company! Doooohhhh!
Posted by: lincoln | April 1, 2007 12:06 AM
This is an example of what happens when someone gets so fixated on an idea that they can’t stand to lose an argument over it.
Here’s a tip for the denialist fanatics: Just because a concept is acceptable to YOUR mind doesn’t mean it is actually true. You may be suffering from psychotic delusions.
So stop denying the real causes of disease, Dale!
To respond to Chris Noble’s comment #64:
Norm Letvin has an M.D., but no Ph.D. – his huge and highly respected lab is, as such, more impressive than otherwise. I thus believe that Lynn Margulis’s reference was not an insulting one, or if it was, was rather accurate. As someone who personally knows him, I’d also say his sense of humor would tend towards finding such a appellation amusing in its truth, not insulting.
btw, Margulis’ sad endorsement of 9/11 kookery was covered in a newspaper article last year
http://www.dailyhampshiregazette.com/storytmp_v6.cfm?id_no=57821
What is that supposed to mean, Dr Frankenstine?
Dear Lynn Margulis,
interesting blog. I would like to thank you for standing up for science and all the scientific principles that humanity has fought long and hard to establish.
please keep doing so.
With best regards
Fritz Kohle
Th sfl mssg