Dean's World

dean,

found this on isiknowledge.com (may require a university subscription, but google scholar would probably work just as well) using HIV AND T cell as the search string.

Title: Mechanisms of CD4(+) T lymphocyte cell death in human immunodeficiency virus infection and AIDS
Author(s): Alimonti JB, Ball TB, Fowke KR
Source: JOURNAL OF GENERAL VIROLOGY 84: 1649-1661 Part 7, JUL 2003

i'm no biologist, and can't vouch for the journal, but the abstract (pasted below) generally describes the function HIV plays in accelerated T-cell apoptosis. The article is a review overviewing several papers and experiments which detail this process.

here's the abstract:

AIDS, caused by the retroviruses human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2), has reached pandemic proportions. Therefore, it is critical to understand how HIV causes AIDS so that appropriate therapies can be formulated. Primarily, HIV infects and kills CD4(+) T lymphocytes, which function as regulators and amplifiers of the immune response. In the absence of effective anti-retroviral therapy, the hallmark decrease in CD4(+) T lymphocytes during AIDS results in a weakened immune system, impairing the body's ability to fight infections or certain cancers such that death eventually ensues. The major mechanism for CD4(+) T cell depletion is programmed cell death (apoptosis), which can be induced by HIV through multiple pathways. Death of HIV-infected cells can result from the propensity of infected lymphocytes to form short-lived syncytia or from an increased susceptibility of the cells to death. However, the apoptotic cells appear to be primarily uninfected bystander cells and are eradicated by two different mechanisms: either a Fas-mediated mechanism during activation-induced cell death (AICD), or as a result of HIV proteins (Tat, gp120, Nef, Vpu) released from infected cells stimulating apoptosis in uninfected bystander cells. There is also evidence that as AIDS progresses cytokine dysregulation occurs, and the overproduction of type-2 cytokines (IL-4, IL-10) increases susceptibility to ACID whereas type-1 cytokines (IL-12, IFN-gamma) may be protective. Clearly there are multiple causes of CD4(+) T lymphocyte apoptosis in AIDS and therapies that block or decrease that death could have significant clinical benefit.

hope this helps.

Dean,

No time to search Medline right now, but I did Google a bit and found this site:

http://discoverysedge.mayo.edu/hiv_cellular_killing_fields/

It says that Dr. Badley recently edited a book about this very subject. It doesn't give the title or the publication date, so I've just emailed them for this information. I'll post it here when I have it. Of course, it's a book and not a series of peer-reviewed papers, but I'm sure the peer-reviewed papers will be cited therein.

hank,

In English, this means that HIV doesn't kill t-cells.

but it has been proven that HIV proteins kills so-called observer cells. cells in the immediate vicinity of an infected cell, while preserving the infected cell itself. at least that's my naive understanding. open to corrections.

HIV isn't poliovirus and since the properties of the two viruses are very different, the 'proofs' that poliovirus causes polio aren't going to be the same as the proofs that HIV kills T-cells.

So before I bother to go looking for references for you, it would be helpful to know specifically what you're looking for; what you would consider definitive proof.

Dale

Dale: Before you go looking for references for me? You mean you don't know such a paper exists?

Don't mealy-mouth it man. Give me the fucking paper that demonstrates that HIV kills t-cells, one that you will personally stand by and say, "yes, any grad student or recently-minted PhD in biology will be able to read this and say it's the definitive proof."

Or does the definitive proof not exist?

Actually I'll just admit it: I believe the definitive proof does not exist, and that you can look for weeks, months, or years and you will not find it. But go ahead, prove me wrong. Give me the paper you will personally stand by and say, "read this, this proves it!"

Elizabeth: I've been asking the question for about 15 years now, and others with vastly more qualifications than me have been asking it longer.

You've more or less admitted the truth though: definitive evidence that HIV kills t-cells, or any cells at all, simply does not exist.

Somehow, by some completely unknown mechanism, it is believed that HIV infects a cell and then kills surrounding cells without killing its host. No one can tell you how this happens, but we're sure it happens because... because.... well because all these people have studied it you see, and therefore... therefore...

Therefore nothing. It becomes circular logic--all these people have studied it and are baffled by it, but the basic hypothesis is sound because all these people have studied it.

Yes, you can cite the classic papers in all those cases. Koch's postulates have been around for a long time, and in the case of every well-known virus but HIV you can point to the definitive studies.

So to turn it around on you: what possible evidence could someone show to you that would make you admit that the hypothesis is shaky?

You won't find one. Don't bother looking.

You'll find a bunch of theories--most of which are good ideas--but you're unlikely to find an article will definitive proof.

::the above is a cop out on my part b/c I'm too tired to look::

Hope things are going well, Dean.

-Jeremy
Slave to MUSC

The most obvious piece of evidence which would make me doubt HIV causes AIDS would be a lack of strong correlation between infection with HIV and CD4 T-cell depletion. In any given population, if another factor was more predictive of immunosuppression (such as, in drug users, amount of recreational drug use is more predictive of persistent low T-cell counts than HIV status) that'd be pretty strong evidence that at least in that population one of the alternative explanations was a better fit for the evidence.

So hit me, ya got a study like this?

Do you know where I can get these two articles ?


Marx, Jean L. Strong Candidate for AIDS Agent (May 4, 1984) Science 224 :475-477

Marx, Jean L. More progress on the T-cell receptor (May 25, 1984) Science 224: 859-860

"That's no answer because there are tens of thousands of papers which talk about this. Where's the one that simply documents in clear and unequivocal fashion how this virus works?"

Isn't that moving the goal posts?
You ask for a demonstration that HIV kills T-cells, but if it doesn't explain how, it doesn't count?

dean,

it wasn't a random medline search. you said you'd like a good paper that you could order. i'd say that review is probably as good as any you're likely to find. like i said, i'm not a biologist, but i'd be willing to stand behind the paper until someone can give me a reason to do otherwise. that paper doesn't report on any new experiments, but collects the results of several earlier papers (sort of the in toto thing you were getting at). if you want it on a silver platter, then i guess wait until someone with a virology degree or biochemist or something chimes in. if you're willing to do a little work, then this is a place to start digging, is all i'm saying.

Methinks many of you are misinterpreting our clever friend Dean's request.

The question -- Where is the paper that demonstrates HIV kills T-cells? -- is a good one.

Maybe there is a paper, maybe not. The scientific literature on the subject is vast.

But, that's not the point.

The point is -- Why do all these smart, polite, articulate folks believe that HIV kills T-Cells, without a factual basis to support the belief?

Example: The reason I believe smoking cigarettes causes cancer is because I have reviewed the extensive works in the scientific literature of Sir Richard Doll, particularly his 1951 seminal paper linking cigarettes to lung cancer.

I think this is a general scientific principle. Review the papers, review the facts, before drawing conclusions. I don't think defenders of HIV are exempt from this general scientific principle.

Mr. Henry (just call me Hank) Barnes

“Why do all these smart, polite, articulate folks believe that HIV kills T-Cells, without a factual basis to support the belief ? “

Perhaps because this kind of recurring information keeps showing up:

“...there is a very dynamic situation in HIV-infected people involving continuous infection, destruction and replacement of CD4+ cells. Billions of new CD4+ cells are produced, infected and killed each day.

These data suggest a return to cellular killing (although predominantly through apoptosis and immune-mediated killing rather than cell fusion) as a direct cause of the CD4+ cell decline in AIDS. “

“This (direct cell killing)) was the earliest mechanism suggested, based on the behaviour of laboratory isolates of HIV. Cell fusion resulting in syncytium formation is one of the major mechanisms of cell killing by HIV in vitro. However, different isolates of HIV vary considerably in the extent to which they promote the fusion of infected cells. Subsequent experiments suggested there may not be sufficient virus present in AIDS patients to account for all the damage seen, although killing of CD4+ cells may contribute to the overall pathogenesis of AIDS in some circumstances. Recently, it has become clear that up to half of the CD4+ cells in the body may be infected with HIV, so the idea of direct cell killing has been re-examined, but in light of induction of apoptosis (see below) rather than by cell fusion. Indirect effects of infection, e.g. disturbances in cell biochemistry and lymphokine production may also affect the regulation of the immune system:

However, the expression of virus antigens on the surface of infected cells leads to indirect killing by the immune system (NK/CTL/ADCC) - effectively a type of autoimmunity. Recently, this hypothesis has been resurrected as a result of more accurate quantitation of virus load and replication kinetics in infected individuals (see below).”

And these topics are still on the table:

Antigenic Diversity:
Superantigen Theory:
T-cell anergy:
Apotosis:
TH1-TH2 Switch:

Dean,

There are a few examples in the history of science in which one can point to a seminal paper (generally identified as such 20 or 30 or more years after the fact) that changed a field of study but in many cases it is the cumulative work of many that is important. So again I would ask that you specify these papers you consider difinitive proof that poliovirus causes polio so I can see what you have in mind.

There are dozens if not hundreds of papers showing that in cell culture HIV infected T-cells will die or kill uninfected T-cells. Do you want some of those references? It might be hard to pick just one because they show similar results under different conditions.

Of course you might want to argue that what happens in a petrie dish doesn't prove that the same thing happens in a living organism and that is undoubtedly true. But then again, there are dozens if not hundreds of papers showing that in SIV infected primates or HIV infected humans, T-cell numbers decrease over time with some classes of T-cells being more affected than others. Do you want some of those references? The SIV studies are better controlled being animal studies but if you don't accept the link between SIV and HIV then maybe you'd prefer to see human data? Do those papers demonstrate the mechanism by which HIV leads to T-cell loss? Nope, because you can't ask that question in a living organism. You have to go to the petrie dish where once again you can argue that a petrie dish is not a human being.

In fact, the vast majority of biology graduate students or newly minted Ph.D.s accept the limitations of any biological experiment and accept that the majority of available data says HIV directly or indirectly leads to a loss of T-cells.

Dale

"Rather, my informal look into the issue shows that AIDS was never a big killer in the USA..."

Tell us more, Hank.

ER: Circular reasoning.

McKiernan: Well, there's beeen 524K AIDS deaths in USA since 1981..

That means the total number of AIDS deaths ever recorded amounts to less than 1 year of cancer deaths.

It averages to 23K per year. In a country of 300 million, that's just not very much. Like I wrote earlier, AIDS is much less deadlier than the flu.

Moreover, the deaths peaked from 1987 to 1996, when AZT was the only AIDS drug available. Giving wholesale doses of cancer chemo (which is what AZT is), probably, in my estimation, made matters much worse.

Of course, I could be wrong.

Barnes, Hank

Dean, you sure about Pauling and polio?
I can't seem to find anything like that in searches on polio or Linus Pauling.

Ah Hank, the world would be a far simpler place if biological organisms only behaved in the way you 'think' they should behave.

What's been known since very early on about AIDS is that patients exhibit a progressive loss of a particular class of T-cells. That is not speculation, that's an observation. You say they can't be dying ... so where do you think they go? Perhaps the tooth fairy has a sister who spirits them away?

Dale

A note came in from Liam Scheff I thought I'd forward along:

—[start Liam's response]—

First from Nature in 2001 - Dr. Joseph McCune; "We still do not know how, in vivo [in the patient], the virus destroys CD4+ T cells… Several hypotheses have been proposed to explain the loss of CD4+ T cells, some of which seem to be diametrically opposed."

LINK

The Second from Nature Medicine in 2003 - cited in "The House That AIDS Built" 2004 -

Stevenson, Mario. HIV-1 Pathogenesis. Nature Medicine, HIV Special. July 2003. Vol.9, No. 7. 853-861.

LINK

In July 2003, the esteemed science journal Nature Medicine published an article called “HIV-1 Pathogenesis” by AIDS researcher Mario Stevenson of the University of Massachusetts Medical School. The article was part of its “20 years of AIDS science” special edition.(6)

From the introduction:

"Despite considerable advances in HIV science in the past 20 years, the reason why HIV-1 infection is pathogenic is still debated... considerable efforts have gone into identifying the mechanisms by which HIV-1 causes disease, and two major hypotheses have been forwarded."

According to Stevenson, twenty years and 118 billion dollars in AIDS research (“considerable efforts”), have given no reliable proof as to how HIV might cause disease (“the mechanisms” by which HIV is presumed to be “pathogenic”). While it is always claimed that HIV is proven to cause illness, Stevenson spends the bulk of his review article pouring over what he describes as two “major hypotheses”that try to describe how HIV might work.

In science, a “hypothesis” is an idea or proposal about how something might work. A hypothesis isn’t a fact, it’s a guess that a scientist tries to prove is accurate and true. If a hypothesis fails, it’s discarded, so that new, better, more accurate ideas can be heard.

In the article Stevenson explains that we don’t know how HIV might damage, let alone kill cells, “…it is debatable whether lymphocyte [white blood cell] damage is due to the direct killing of infected cells...” and we don’t have any idea how HIV affects immunity, “…processes contributing to the immune activation state in HIV-1 infection are not well understood..." The HIV hypothesis states absolutely that HIV kills T-Cells, but Stevenson tells us the underpinning of this assertion is still debated.

Stevenson concludes the paper by returning to the main theme – the vast unknowns in HIV science:

"There is a general misconception that more is known about HIV-1 than about any other virus and that all of the important issues regarding HIV-1 biology and pathogenesis have been resolved. On the contrary, what we know represents only a thin veneer on the surface of what needs to be known."

Stevenson tells us that after 20 years of research into the various HIV hypotheses, we know "a thin veneer," about HIV's "biology and pathogenesis," that is, what HIV might look like, how it might work, and, as such, how - and therefore if - it is responsible for AIDS illnesses. We’re told that it is, but according to Stevenson and “Nature Medicine,”, we don’t have proof.

By the standard of “First do no harm”if we don’t know how a molecule works (HIV or any other), then it is unethical to treat any presumed HIV positive person with extraordinarily toxic, and often fatal pharmaceuticals, which the manufacturers themselves admit, do not cure AIDS.

In addition to their long list of serious and potentially fatal side-effects, all major AIDS drugs also bear a version of this printed warning:

“This drug will not cure your HIV infection…Patients receiving antiretroviral therapy may continue to experience opportunistic infections and other complications of HIV disease…Patients should be advised that the long-term effects are unknown at this time.”



—[end Liam's response]—

So. Make of it what you will. That matches what I thought was the state of the art in HIV--lots of wild-ass guesses as to how it killed T-cells, nothing firm or reliable despite 20+ years of research. That otherwise the data is based on statistical correlations that don't seem to stand up very clearly.

When they isolated the polio virus, they took it out of a sick human, isolated and purified it, put it into a chimp, and the chimp got polio, then took it out of that chimp, purified it again, and put it in another chimp and got that chimp polio--just like chimps get sick from all human viruses except HIV. That's the work that made Linus Pauling and his partner (who I ironically can't remember) famous, along with their later vaccine. You find that with all the other major viruses too, so far as I know. [shrug]

The papers I've seen claiming HIV kills t-cells all seem very tentative. But maybe I'm wrong. I'm willing to look at the paper which shows in vitro, clearly and unequivocally, that HIV-infected cells kill non-HIV infected cells at a rate that cannot be explained by anything other than HIV being present. But you or someone has to stand by it and say, "yep, read this, no question, SOMEHOW HIV is killing those cells since without it present those cells just don't die at anywhere near the same rate." Or something on that level.

Because we already admit (I hope) no one knows how it happens in vivo. So where's the rigorous proof it does so in vitro at least?

Read the Stevenson paper rather than Liam's carefully selected quotes. You'll find lots of references within it to HIV killing T-cells. The unknowns are not whether HIV leads to the killing of T-cells but the relative importance of the various mechanisms by which it is apparently capable of doing so.

Dale

Sorry for late response, you know, work, life, girls,...:)

Well, ER, you seem awful full of yourself with vast google knowledge of 3 very prominent viruses:

avian leukosis virus (some types)
feline leukemia virus
foamy viruses

Hmm. Wait. Lemme check the numbers of annual causes of death in our beloved country of 300 million: I see cancer, heart attack, stroke, yup, all the main ones. Hey, there's flu &pneumonia!

But, wait lemme see how many people died from

avian leukosis virus (some types)
feline leukemia virus
foamy viruses.

I see ...ZERO. Zero deaths out of 300 million people. More people died from lightning strikes than the 3 stupid viruses you named. But, hey, they kill cells, right? LOL

You are an outlier. You need to show me a human retrovirus that has an iota of clinical relevance. There are none. That is why HIV is a gross outlier and unlikely to do all the magical, mysterious dirty work it purports to do. It belongs to a class of viruses, that are basically inert.

Call me if your cat ever comes down with Feline Leukemia Virus -- we'll start her on kitty AZT immediately:)

Barnes, Hank

Okay, Hank. Here's one experiment that shows HIV infected cells can kill uninfected. Cells were isolated from an uninfected patient and the CD8+ T cells removed (that was done because it was already known that CD8+ T cells will kill infected CD4+ cells). The cells were then stimulated with chemicals to make them actively dividing so they could be infected with HIV. More than 70% of the cells were infected after 3-4 days. Uninfected CD4+ Tells were labeled with radioactive chromium and then added to the same number of unlabeled uninfected or unlabeled infected cells. Chromium release (which is an assay for cell killing) was measured at various times. When labeled uninfected cells were mixed with unlabeled uninfected cells, the maximal cell killing observed was less than 1%. When the labeled uninfected cells were mixed with infected cells, maximal cell killing was about 20%. The authors interprete that experiment to show that HIV infected cells kill uninfected cells. How would you interprete it Hank?
Dale

Hank, no virologist or immunologist would ever agree that infecting cells is the only way a virus can kill a cell. Most if not all disease causing viruses that infect human cells causes an immune response. You remember immune responses, right? Part of an immune response is that CD8+ T cells, macrophages and natural killer (NK) cells, in response to signals from the infected cell, migrate to the site of the infection and kill the virus infected cell. That is indirect killing of a virus infected cell. I'd like you to name me a real viral disease in which that doesn't happen.

Hank,

If you can't understand the relevance of multiple examples of disease-causing retroviruses killing cells in non-human animals to the claim, "retroviruses don't kill cells," then it's difficult to see how discussing it further is going to enlighten you. Similarly, if you can't read and understand the multiple links I've already posted describing viruses causing disease through mechanisms other than lysis, you're not going to be able to read and understand any others I post. You are either intrinsically or willfully unable to follow an argument, which is unfortunate because it makes it a lot less entertaining to discuss serious issues with you. Thanks for prompting me to find those links, I learned a few things from them, but I'm bored now.

Dale: I will get those papers and read them carefully.