Re: "HIV" and KS 18 August 2004
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Nicholas Bennett,
Infectious Disease Postdoc/Clinician
Department of Pediatrics, University Hospital, Syracuse NY

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Re: Re: "HIV" and KS

The Perth Group continue yet again to post without thought of what they are saying - it is clear why they have had trouble getting some of their work through peer review!

I did respond precisely to the Perth Group's request regarding RT characterisation. I said
"I would perform other experiments: firstly using uninfected cultures in parallel to compare endogenous levels. Secondly I could characterise the enzyme in terms of buffer specificity, so I wouldn't just be looking at pH 7.8 and Mg 5mM, but at a range of magnesium concentrations and acidities to distinguish it from other enzymes."

Montagnier did exactly this, hence demonstrating proof of RT versus inefficient "RT" activity through mitochondrial DNA polymerase. The Perth Group state that he didn't do so: why? Are they purposefully ignoring evidence that would counter their already tenuous arguments?

The Perth Group then go on to say:
"We never said that oxidation is synonymous with stimulation. We claim that for stimulation oxidation is absolutely necessary"

Which is just as ludicrous, if not practically saying that oxidation is synonymous with stimulation. Stimulation of cells can quite easily be explained through signalling cascades such as tyrosine kinases, with no need for unspecific oxidation to be involved. The "invention" of signalling cascades is an unfortunate fact of cell biology, and I was urge the Perth Group to educate themselves on this fascinating and extraordinarily complex science, rather than rely on over-simplistic thought-experiments.

Oxidation is not required to explain cell death due to over stimulation. It is well known (at least, among those who have studied even rudimentary cell biology or genetics) that multicellular organism cells are primed to undergo apoptosis unless they recieve suitable stimulation. This is to prevent uncontrolled cell growth (cancer, in layman's terms). Similar to the loss of supportive signals, over expression of certain oncogenes can result in cell death: the loss of monitoring processes is required for the oncogenes to act to cause cancer (the multi-hit hypothesis, extremely well characterised with colon cancer). In the same way mild DNA damage induces DNA repair, whereas large DNA damage also induces cell death, mediated through the same proteins (p53 for example).

If the Perth Group think that cell death through overstimulation (for example) is a random process I suggest they run a simple pubmed search on "caspases" and marvel at the incredible way the cell commits seppuku with a method far more efficient that any man-made drug can induce, and far more specifically than any "oxidative stress".

I never said that stimulation wasn't necessary to activate HIV, I did make clear though that stimulated UNINFECTED cells do not produce HIV. As I said above "...we cannot expect HIV to replicate without NF-kB. It is no coincidence that a T-cell trophic virus utilises the major transcription factor of T cell activation." which clearly states the importance of cell activation affecting the promotor region of the HIV provirus. To say that I said the opposite, and then argue against it, is one example of a strawman argument. They set it up only to shoot it down.

I have found no evidence that PHA is an oxidising agent, other than the Perth Group categorising it as such because it is a mitogen. Such circular reasoning is something they accuse others of doing! If they can provide direct evidence that PHA is an oxygen/radical donor then I would be interested to see it.

I'm amazed at their use of a single speculative paper from 1983 calling into question whether the T cell "marker" of T4 is in fact functional. This is crazy! The function of the CD4 molecule in acting as a co-receptor for MHC class II antigen presentation molecules in coordination with the T-Cell Receptor is one of the cornerstones of immunology, under pinning every specific immune reaction from IgG to cytotoxic T cells. If they had any basic training in immunology they would know this, and from their current level they are trying to argue against one of the most complicated immune dysfunctions of current medical science!

The Perth Group forget one very obvious point in their conclusion. HIV infection itself is a stimulating agent. The mechanism of AIDS, if I may be so bold as to spell it out for them, is roughly as follows.

HIV infection -> immediate CD4 cell loss through:
Trafficking to Lymph nodes (activated T cells traffic)
Cell death (HIV is cytotoxic to T cells)

Immune responses then become established:
Cell death due to HIV decreases, immune activation decreases.

Chronic "latent" asymptomatic phase:
Ongoing immune activation keeps cells over activated and therefore replicating and trafficked towards lymph nodes
HIV preferentially infects and replicates in activated T cells. The biological situation is therefore supportive of continued HIV replication, assisted by the fact that it is an integrated provirus in many cells.
Infection of inactive cells (T and macrophages) leads to proviral reservoir. Later activation through antigen recognition (HIV or new infection) leads to HIV activation and cell death. Therefore HIV SELECTS for those cells responding to itself or new infections (a very effective immune-deficiency causing process).
Cell signalling is altered as cell cycle arrest is mediated by HIV, and progression through the cell cycle is required for successful cytokine production.
Lack of correct cytokine environment reduces T cell replacement from the thymus (hypothetical at the moment, observational evidence only).
CD8 killer T cells preferentially destroy HIV-infected CD4 T cells.

All the above leads to: selective loss of activated (useful) T cells, cytokine skewing through chronic activation, premature immune system aging (seen in many other viral infections), gradual decline in immune repertoire and eventual thymic exhaustion. This is well documented in the literature of the last 10 years, it is not my fault if they have not kept up with it.

As the available T cell repertoire (number of antigens it can recognise) is reduced to the point where HIV can no longer be controlled, the infection becomes overwhelming. It is at this stage that AIDS usually occurs.

The mechanism above explains a great many things, including biphasic T cell responses to HAART (trafficking from lymph nodes, then gradual thymic replacement), gradual immunological repertoire narrowing, and the poor responses from very end-stage disease to treatment (in terms of restored repertoire).

It is from such immunological measures that KS can be shown to be cured by anti-HIV drugs. The Perth Group have presented no evidence that the antiretrovirals adversly affect mortality, and in fact there is overwhelming evidence to the contrary! KS can certainly be treated by conventional anti-cancer therapies, but most other cancers cannot be treated by anti-HIV therapy. Most notably lymphoma associated with HIV is unaffected by HAART (no doubt because it is not associated with a secondary viral infection, like HHV8).

If KS caused by immune deficiency was "discounted as far back as 1982" then why does the National Cancer Institute in 2004 say that "The incidence of KS in immunosuppressed renal transplant recipients has been estimated at between 150 and 200 times the expected incidence of this tumor in the general population." [1] They also discount several other Perth Group statements, with recommendations such as: "essential components of an optimal [AIDS-related] Kaposiís sarcoma (KS) treatment strategy include antiretroviral treatment" and "In epidemic KS, the already profoundly depressed immunologic status of the host limits the therapeutic usefulness of systemic chemotherapy".

I am certain that others will disagree, but personally I am of the opinion that a national institute acting on the basis of science I agree with, holds more weight that that of a disparate group with an ongoing and proven track record of misinterpretation, misunderstanding and obfuscation.

Levy's 20 year old comment "However, if immunosurveillance is involved in this biological event, why are not other common cancers such as those of the lung, colon, and breast, and leukaemias also observed?Ö"

is explained by the more recent knowledge that KS is caused by a secondary virus infection, whereas the others are not. Similarly cervical cancer, caused by HPV infection, is also increased in AIDS patients. There is no inconsistency here, in fact the entire story is extraordinarily consistent! Clearly the immune surviellance of tumours such as colon, lung and breast is different in some way from those of virally-caused tumours, or the oncogenic potential is overwhelming for the normal protective cellular mechanisms. This difference is a pointer to future investigation, but doesn't detract from HIV being immunosuppressive at all.

The statement from the Walter Reed Army Institute is an outlier, since the current and indeed past understanding of KS is that it is in fact enhanced by immune suppression. Similar to the cherry-picked thought-processes of Zagury in 1983 I suggest they discount this in favour of regarding the current understanding of the pathogenesis of KS and other viral cancers.

The Perth Group have the audacity to ask me to read their references properly, when they cannot even do so themselves. They are kind enough to state that long-term HIV cultures can be established by "manipulating the culture conditions", and this is true. I have kept HIV cultures growing alongside uninfected unstimulated cells for nearly 200 days. In a well controlled paper by Yu et al [2] they can clearly see cell death which can only be explained by viral infection. In fact, it can be seen that different virus strains exhibit different cytotoxicities. The paper is available online in Pubmed Central, so those reading along can see that HIV does indeed kill cells directly, and that controls are indeed done in HIV research.

I would counter that in order to have a scientific debate, one must first be a scientist. Additionally it would help if one were educated in the area to be discussed. Through their manipulation, ignorance and selective quoting of the literature, the Perth Group hardly appear as scientists. Additionally their blatant demonstrations of refusing to acknowledge past mistakes, learn new facts and update their understanding of what are sometimes fundamental scientific principles throws doubt on their willingness to be educated. All of this is documented in the Rapid Responses above.

Ignorance is forgiveable, providing one is willing to learn. Willful ignorance in science is tantamount to professional suicide.

1. http://www.cancer.gov/cancertopics/pdq/treatment/kaposis/HealthProfessional
2. Yu et al. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10237-41. "Killing of primary CD4+ T cells by non-syncytium-inducing macrophage-tropic human immunodeficiency virus type 1." http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=7937869

Competing interests: None declared