Where is the evidence that "HIV" is causally related to KS? 20 August 2004
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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

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Re: Where is the evidence that "HIV" is causally related to KS?

Where is the evidence that "HIV" is causally related to KS?

In his rapid response: "Kaposi's Sarcoma and the Perth Group", Christopher Noble quoted us: "The difficulty we encounter in our attempts to publish in peer reviewed journals can be best illustrated by an example. In 1988 we submitted to The Medical Journal of Australia a paper entitled "HIV and Kaposi's Sarcoma – a questionable relationship", in which we had argued that HIV could not be the cause of KS."

Christopher Noble responded: "This is the first, hmmm, misrepresentation".

From the beginning of the "HIV" era we have argued that "HIV" could not be the cause of KS. We continued to do so. Where is the "misrepresentation"?

Christopher Noble wrote: "The Perth Group also misrepresent their own claims. They actually claimed that KS was not caused by any infectious agent but rather that it was caused by nitrite inhalants and semen. If the Perth Group want to claim that they have been vindicated they are sadly deluded."

It is true that at the beginning of the AIDS era we put forward the hypothesis that the "AIDS" KS is caused by repeated exposure to high levels of nitrites, semen or by these agents acting synergistically. We have given a mechanism by which they may cause their effects which leads to predictions about prevention and treatment of KS (Ref. Reappraisal of AIDS; Int. J Radiat Oncol Biol Phys…) We still stand by this hypothesis. However, although there is evidence in the literature which supports our theory, we have never claimed that we have been "vindicated".

Would Christopher Noble please tell us what makes him to think that we "misrepresent" our "own claims"?

Christopher Noble wrote: "An infectious agent KSHV/HHV-8 was subsequently discovered which is found in all four types of KS and the evidence for its involvement in KS is overwhelming, if not conclusive….The Perth Group claim that they critically analyse the scientific literature. You would then expect that they systematically cover all the literature rather than selectively quoting from isolated papers. Try looking on their website for any mention of KSHV/HHV-8.

site:www.theperthgroup hhv8 OR hhv-8 OR kshv"

There is no mention of KSHV/HHV-8 in our website. There is a very good reason for it. Despite its name, Kaposi's Sarcoma Herpes Virus (KSHV), nowhere in the scientific literature is there any evidence which proves that KSHV/HHV-8 causes KS.

According to Christopher Noble the view expressed by one of the Medical Journal of Australian reviewers that KS is a "fascinating manifestation of HIV infection",

"it seems [is] unanimous". He also claims that the view expressed by another reviewer of the same paper: "Unfortunately, their hypothesis is now completely untenable. We are fortunate that new information discussed at the recent International AIDS Conference in Florence gives us a much better idea of the pathogenesis of Kaposi's Sarcoma in HIV infection, evidence demonstrating that activation of the tat gene with subsequent effects on the production of IL6, produces both the proliferation of endothelial cells responsible for KS and the elicitation from those cells of an angiogenic factor as well as the polyclonal gammopathy seen in the disease, takes us very far down the path towards an understanding of these problems and far away from the hypothesis suggested by the West Australian scientists";

Is, "yep, unanimous"

Our answers to the reviewers comments is attached. Concerning Christopher Noble's claim that these views is "yep, unanimous" suffice to mention the originator of the HIV theory of KS, Robert Gallo: "There's a common belief that it's immune suppression that is involved. Our data would argue the opposite – that it's immune stimulation. You can have Kaposi's in the absence of immune suppression….The first thing I can tell you is that we've been able to regularly culture from Kaposi's tumours what pathologists say is a tumour cell. We asked: What is the role of HIV in all this? And we found that inflammatory cytokines…were the very likely initiatory events in creating this cell. We said, "Oh, the role of HIV is likely to be in increasing these inflammatory cytokines" But we have learned – this should be of interest to everybody that isn't completely married to HIV – that the inflammatory cytokines are reportedly increased in gay men even without HIV infection. Inflammatory cytokines are usually promoted by immune activation, not by immune suppression. So here was a paradox….So the inflammatory cytokines may be increased by HIV, but I wish I knew what else was increasing them before a gay man was ever infected with HIV. Maybe it's nitric oxide, maybe it's a sexually transmitted virus, maybe it's all of them, maybe it has to do with rimming because it's immune stimulation with non-specific infections….The nitrites could be the primary factor. What if the nitrites had the ability, interacting with endothelial cells, to produce a tremendous amount of 'X', of inflammatory cytokines?….But even if we have no knowledge of what the etiologic agents are, when I study pathogenesis of HIV-KS, I come to the importance of inflammatory cytokines, endothelial cells, and the TAT protein. I used to think all the time, HIV is also producing the increase in inflammatory cytokines, but it's only in the past few months that I've learned that in gay men, there's an increase in these same inflammatory cytokines before HIV infection. Why? I don't know…."

{ref. John Lauritsen: NIDA Meeting Calls for Research into The Poppers-KS Connection. New York Native, Issue 13 1994}

Christopher Noble quoting us wrote: "Our paper was rejected even after the 1992 publication, in Lancet, by the CDC researchers where they presented evidence against the claim that the cause of KS is HIV[1]."

Christopher Noble replied: "Again they misrepresent history. This paper Beral et al argues that KS is caused by an as yet unidentified sexually transmitted infection whereas the Perth Group claim it is caused by poppers and semen. The current evidence supports Beral et al (HHV-8 was later identified) not the Perth Group."

Valerie Beral et al wrote: "Suggestions that Kaposi's sarcoma might be a manifestation of HIV infection itself are not supported by the reports of Kaposi's sarcoma in HIV-negative homosexuals; nor by the 20-fold differences in risk of Kaposi's sarcoma…"

Comparing Valerie Beral's et al statement with the quote from us, what scientific reasons does Christopher Noble have in support of his claim that we "misrepresent history"?

Once Valerie Beral and her colleagues concluded that HIV plays no role in the development of KS they put forward the hypothesis that: "….Kaposi's sarcoma in persons with AIDS may be caused by an as yet unidentified infectious agent, transmitted mainly by sexual contact." (A hypothesis which still remains to be proven. Even if HHV-8 is "identified" in all KS patients, identification is not proof for causation). They also added: "Although the data are consistent with an infectious cause for Kaposi's sarcoma, other explanations need to be considered. Nitrite inhalants (poppers) or other substances to which homosexual men have been preferentially exposed have been suggested as a cause of Kaposi's sarcoma….Kaposi's sarcoma has been associated with both sexual practices and the use of poppers." {ref. Beral}

Christopher Noble quoted us: "At present it is generally accepted that HIV plays no role either directly or indirectly, in the causation of KS", and replied

"Hello, anyone there? Have you read the literature lately? Just try a search at pubmed with the terms "HIV tat KS". I don't know where the Perth Group get their ideas about what is generally accepted."

If "Anyone there" does "a search at pubmed with the terms "HIV tat KS", will realise that although the "HIV" experts spared no effort to prove that the "HIV tat" is causally related to KS, no such proof exists. Even if a "Tat protein" is proven to cause KS, before one claims a causal role of "HIV" evidence must exist which shows that the "Tat protein" is a constituent of "HIV". This in turn requires prior proof for the existence of "HIV".

All the "HIV" experts, including Robert Gallo claim that in 1983 Luc Montagnier and his colleagues have proved the existence of "HIV". We have repeatedly asked Christopher Noble if Montagnier has proven the existence of "HIV". Christopher Noble did not respond. Unless Christopher Noble provides evidence which, in his view, proves the existence of "HIV", any effects he attributes to "HIV", including KS, are nothing more than science fiction.

In conclusion, in 1988 when our paper was rejected by the Medical Journal of Australia at the reviewers recommendations, like today, no evidence existed that KS was either a direct or indirect, "fascinating manifestation of HIV infection".

Since: (a) there is no evidence that "HIV" is causally related to KS; (b) according to the "HIV" experts the cause of AIDS is "HIV";

why is KS still an AIDS indicator disease ?

Furthermore, since: (a) the retroviral theory of AIDS cannot account for one of the two diseases for which it was proposed to explain; (b) the basis for Gallo's retroviral theory of AIDS was KS;

then, any scientist worth his salt has no choice but to at least ask for its reappraisal, if not for it's abandonment.

ANSWERS TO THE REVIEWER'S CRITICISMS

PARAGRAPH 1

As this paragraph demonstrates the referee realises that there are two sides to the debate on the pathogenesis of AIDS. Naturally I am only offering one of them as the other side has been rigorously presented in The Medical Journal of Australia. Notwithstanding the referee's assertion that the argument has not been constructed from current literature, I draw your attention to the fact that of a total of 47 references, there are 5 (11%) 1988 references and 14 (30%) 1987. Some of our references go back to the 1970's because the scientific basis of retrovirology was established in that period. Presently much of the current debate is flawed because the participants are unaware of or ignore the basic principles of retrovirology. To talk therefore about HIV without understanding the other retroviruses is like a blind man trying to solve Rubik's cube.

Morevoer we showed our manuscript to several Medical Journal of Australia readers within this Hospital and they had no difficulty dissecting the arguments presented. We feel that the referee underestimates the intellectual capacity of the Medical Journal of Australia's readership.

PARAGRAPH 2

In paragraph 2 the referee has noted that there is an overlap in the basic position taken by the two papers. However two different subsets of evidence are presented to support the view expressed.

KS constitutes only a very small part of the evidence against HIV as the causative agent of AIDS. For some unknown reason the expert ignores all other evidence. The reference by Haverkos which the referee cites is quoted in paragraph 2 page 4 in 88-1534. In that paragraph of the manuscript I claim that KS has a high incidence in organ transplant recipients and that the clinical features of AIDS KS differ from those in all other KS patients and give two references including that of Haverkos to support my claim. If the expert would have considered the two references together as they are given, and read them carefully and not desultorily, I am certain he would have reached the same conclusion.

Haverkos states "An unusually high rate of KS has been reported among renal transplant recipients".

In the second reference quoted by me one reads:

"Four major groups of patients with KS have been reported until now:

(1) the classic form of KS (CKS), usually found in old Caucasians, mainly of Mediterranean or Eastern European origin, presenting a papulonodular appearance of the disease, running in a relatively benign indolent course of 10-15 years; (2) the iatrogenic form (IKS) observed in immunosuppressed patients, mostly renal transplant recipients, but also present in systemic lupus erthematosus (SLE), rheumatoid arthritis (R.A.) and other diseases treated with high dose immunosuppressive therapy; in this kind of patient the lesions often remain localised to the skin but a widespread dissemination with mucocutaneous or visceral involvement is not uncommon;…..(4) the last type of KS is the one recently observed in AIDS patients, called epidemic KS (EKS); this new variant presents itself in a more aggressive form involving the mucocutaneous district, the gastrointestinal tract and lymph nodes with a rapidly progressive course, sometimes fulminant and with an overall survival of 18 months".

Many other authors support my "arguments". For example in a paper by Safai et al one reads:

"Table I. Kaposi's sarcoma features

Classical KS AIDS-KS

Mean age years 63 39

Sex ratio 10:1 male mostly male

Distribution Africa, Europe, USA USA, Europe, Haiti

Skin lesions Lower extremities Head and neck, trunk

Lymphadenopathy Rare (except African Frequent

children)

G1 involvement Rare Frequent

Biologic behaviour Slow and indolent Aggressive and fulminant

Associated diseases Lymphomas 01, lymphoma

Immune deficiency Borderline Severe and progressive

Median survival 13 years 18-22 months"

The same authors consider, "important to note that most patients with AIDS do not develop KS and that KS is seen mostly in homosexual men, again implicating other factors in the homosexual life-style to be involved in the pathogenesis of this neoplasm". (Safai et al, Antibiot, Cehmother. Vol. 38; 80; 1987).

One additional reason for quoting Haverkos was his detailed discussion of the epidemiological evidence regarding KS in AIDS patients. His data support my claim that nitrites acting synergistically with sperm and not HIV are the cause of KS in homosexuals: "Multivariate analysis showed that the variable most strongly associated with KS was using more than four "hits" of nitrites per night of use".

We agree with the referee that the epidemiological, immunological and cellular literature concerning the pathology and pathogenesis of KS are interesting. However, from the same literature we also know that some of the great retrovirologists do not consider the relationship between HIV and AIDS as proven beyond doubt and that none of them are of the opinion at present that KS is a "fascinating manifestation of HIV infection", as the referee claims.

· Baltimore, the retrovirologist who shared the Nobel prize with Temin for their discovery of RT, speaking on HIV and AIDS states: "Very few basic laboratory experiments are done. Most efforts are in the form of observations and hypotheses". (JAMA, August 19, 1988).

· "HIV IS NOT THE CAUSE OF AIDS". Duesberg, a molecular biologist who "probably knows more about retroviruses than any man alive". (Science 241; 514; 1988).

· "Kaposi's sarcoma is particularly common in male homosexuals with AIDS (48%). In contrast, less than 1% of haemophiliacs and recipients of blood transfusions with AIDS develop Kaposi's sarcoma, and only 2% of drug misusers. These observations suggest that an unknown agent causing Kaposi's sarcoma may be widely prevalent among homosexuals but not among recipients of blood or blood products". Weiss, retrovirologist, Institute of Cancer Research., Chester Beatty Laboratories, London. (J. Clin. Pathol. 40; 1064; 1987).

· "In our system 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 and Burke (Sci. Amer. October 1988 pg. 70). Redfield and Burke are colleagues at the Walter Reed Army Institute of Research in Washington, D.C. Redfield is chief of the section of retrovirology, immunoregulation and immunotherapy and medical director of the clinical virology laboratory. He was recently given the first annual Thomas Parran Award for his work on HIV infection. Burke is a colonel in the Medical Corps of the U.S. Army. He has been chief of the Department of Virus Diseases at the Institute of Research since 1984.

We have carefully read the paper by Nakomina et al which the referee claims "clearly implicates HIV infection of cells in-vitro in production of angiogenic growth factors" and thus presumably in the pathogenesis of KS. Nakomina et al have shown:

1. The medium (conditioned medium = CM) in which T-cells contaminated with HTLV-II (a retrovirus which does not belong to the HIV family of retroviruses) are grown:

(a) contains large amounts of a factor(s) which can sustain the growth of KS cells in-vitro;

(b) also supports the growth of normal endothelial cells. So did other factors.

2. Medium in which HIV-1 infected H9 cells were grown also sustained the growth of KS cell in-vitro but to a smaller degree than HTLV-II CM. However, so did HTLV-I CM, HIV-II CM and more importantly, media from non-infected H9 cells and another leukaemic cell line – HUT78. It is also important to note that the medium from the retrovirus infected cells, including HIV-1, is supplemented with lectins and interleukin-I which could explain, at least in part, the growth activity as the authors found out for Interleukin-I alone. In other words the stimulation of KS cell by HIV-1 CM is non-specific and in fact may have nothing to do with HIV-1 infections of the H9 cells.

Unless the referee considers the non-specific stimulation in-vitro of KS cells by HIV-1 CM as equivalent to the production of angiogenic growth factors, nowhere in the paper is there evidence which "clearly implicates HIV infection of cells in-vitro in the production of angiogenic growth factors".

Let us assume that the authors presented evidence which proves beyond doubt the referee's claims.

This could not have incriminated HIV-1 in the pathogenesis of KS for one simple reason – everybody at present is aware that all cell in-vitro release growth factors including angiogenic factors. This is well illustrated in another paper in the same issue of Science entitled Angiogenic Properties of Kaposi's Sarcoma-Derived Cells After Long Term Culture In Vitro; (Salahuddin et al Science 242; 430-433; 1988).

The authors have shown:

1. Virus free KS cells produce factors that support their own growth and the growth of other cells including endothelium and fibroblast;

2. Non-infected KS cells express potent angiogenic activity;

3. "To test the possibility that a known infectious agent might be involved in KS pathogenesis, we tested the six AIDS-KS cell cultures with specific probes for several human retroviruses and human DNA viruses. No evidence of nucleotide sequences for HTLV-I and II, HIV-1, HHV-6/HBLV, HHV-4/EBV, HHV-5/HCMV, HHV-1 and 2, papova, and polyoma viruses, was found. Nor did we find evidence of such viruses in cell cultures by electron microscopy or by virus isolation techniques".

PARAGRAPH 3

I have in my possession approximately 500 papers (photocopies) on AIDS each of which was scrutinised at least twice and at least as many again (including 5 books) which have been read but not copied. It is possible that I may not judge objectively my own knowledge of "contemporary literature" and for that reason I enclose an appraisal of my knowledge in general and of AIDS in particular by others, including a referee of The Medical Journal of Australia.

If the only impediment to publication is the literary style and not the content, we are quite prepared to make whatever changes are necessary to make them compatible with the Journal. As to the question of targeting the wrong readership – if there are serious scientifically based doubts in relation to HIV on the cause of AIDS, we believe that doctors who are ultimately responsible for the care of these patients represent an entirely appropriate and necessary readership.

In Science, reasoned and informed debate is crucial. Because the question of the precise pathogenesis of AIDS is still unclear then in the interest of scientific honesty the counterarguments to the accepted HYPOTHESIS should be presented to the interested audience – otherwise the pursuit of knowledge becomes a pursuit of fantasy.

Competing interests: None declared