VIRUSMYTH HOMEPAGE


TO FUND OR NOT TO FUND,
THAT IS THE QUESTION:

Proposed Experiments On The Drug-AIDS Hypothesis
To Inform Or Not To Inform, That Is Another Question

By Serge Lang

Yale Scientific Winter 1995


Since Gallo's press conference with HHS Secretary Margaret Heckler in 1984, the HIV-AIDS hypothesis that "HIV is the virus that causes AIDS" has generally been accepted. Some people, notably Peter Duesberg, have pointed to serious difficulties about the scientific basis for this hypothesis, and have proposed another hypothesis, the drug hypothesis, that under certain conditions, involving the quantity and nature of drugs taken over certain periods of time, drug use may be a cause of certain diseases which have been listed by the CDC as AIDS related diseases. I take no position at this time concerning the validity of any of these hypotheses, but I am concerned here with the history of a proposal by Duesberg to perform some experiments to test the drug hypothesis. The bottom line is that the NIH Center for Drug Abuse refused the funding, and the matter was not reported in the scientific press, notably Science, at the time, thus raising two issues: one about the legitimacy of refusing such funding, and the other about the way the scientific community is not informed properly of some events which some scientists regard as important. The documentation I shall provide can also be used to evaluate the verdicts of scientific reviewers concerning the funding of a proposal that goes against accepted ideas.

1. The Proposal

Duesberg filed a grant application to the HHS Public Health Service on 30 August 1993. The purpose of the application was to examine the effect of some drugs (nitrites) on some animals, to see if they cause AIDS-related diseases involving both immunodeficiency, and cancer type diseases. As Duesberg once said, "we'll feed poppers to mice." Duesberg filled in the box asking for "the application's broad, long-term objectives, making specific reference to the health-relatedness of the project" in more standard scientific language, as follows:

From Duesberg's Funding Application

The long-term consumption of nitrite inhalants has been suggested since 1981 as a possible contributing factor to AIDS. Epidemiological correlations have established a dose-response relationship between nitrite consumption and AIDS risk, and the restriction in their use to the active homosexual community correlates well with the restriction of Kaposi's sarcoma in homosexuals with AIDS. Long-term exposure of mice to nitrites can result in immune suppression. However, such toxicological experiments have thus far remained inconclusive, because they have not been carried out at an adequate dose and length of time.

Following and exceeding unfinished studies by others from the mid-1980's, it is proposed here to determine the effects of the long-term inhalation of nitrites on mice (e.g. 6 hrs per day, 5 days per week, for 6 to 24 months). To distinguish between the roles of nitrites as autonomous pathogens and as co-factors of HIV, murine retrovirus-infected and un-infected mice will be studied in parallel. The parameters to be monitored include a) weight loss, b) anemia and lymphocytopenia, c) clinical manifestations of immunodeficiency, particularly Pneumocystis pneumonia, d) evidence for Kaposi's sarcoma. In addition, we propose to study the effects of nitrites on the growth rate of human t-cell lines in culture. Finally we plan to examine the Kaposi sarcomagenic potential of nitrites on rodent cells in culture. Avoiding the toxicity to vital organs, like the lung and the bone marrow, the cell culture system will permit us to test nitrites at higher-than-in-vivo concentrations. This is critical to detect sarcomagenic potential, because Kaposi sarcomas are typically restricted to humans with the highest cumulative lifetime doses of nitrites.

The proposed research would clarify whether immunosuppression and/or Kaposi sarcoma can result from long-term exposure to nitrite inhalants. Public health efforts aimed at AIDS prevention might increase their effectiveness by discouraging the recreational use of nitrites and other psychoactive drugs, thereby lowering the AIDS risk even of those already infected by HIV.

It is not generally realized that the nitrites-AIDS hypothesis (that nitrites play a strong role in causing AIDS) was the first one offered by scientists, dating back to around 1980.(1)

Duesberg's grant application was made to the proper agency, the National Institute on Drug Abuse (NIDA), whose responsibility it is to fund such experiments as he proposed, and which has funded such experiments in the past. In 1988 NIDA even published a monograph entitled "Health hazards of nitrite inhalants" [NIDA 1988]. This monograph dealt with many aspects of toxicity of nitrite inhalants.(2) Among other things it described the strong epidemiological and clinical evidence, as well as experimental evidence resulting from experiments on mice. The evidence from these experiments supported the nitrite-AIDS hypothesis. The NIDA monograph shows that as late as 1988, research into the nitrites-AIDS hypothesis was regarded by some people in NIDA as a legitimate field of scientific inquiry.

According to Duesberg, his proposal was originally solicited by the above monograph's co-editor (and author of one of the articles in the monograph) Harry Haverkos, clinical director of AIDS research at NIDA. Thus Haverkos found it appropriate to NIDA's mission, and according to Duesberg, Haverkos considers unfortunate that no testing of the nitrite-AIDS hypothesis is currently being performed, because he and other toxicologists agree that much evidence indicates an important role for nitrites in AIDS. The preface to the monograph by Haverkos and his co-editor is compatible with this view.

The reviewers of Duesberg's proposal for NIDA wrote a specific positive recognition in connection with the proposal. They asserted (p. 2 of the review): "The major strength of this proposal is that it addresses the important public health problems of whether nitrite abuse acts as a cofactor in AIDS pathogenesis and if nitrites can cause Kaposi's sarcoma in the absence of retrovirus infection."

The NIDA reviewers also explicitly recognized the credentials of the applicants. The proposal involved a collaboration between Duesberg, whose expertise lies in chemistry and retroviruses, and Otto Raabe, an inhalation toxicologist. The above evaluation of "the major strength" of the proposal was followed by an evaluation of the investigators: "In addition, the proposed investigative team has expertise in retrovirus research, inhalation research, and immune cell culture and has the potential to carry out collaborative research in this area." The NIDA reviewers followed up with a similar statement on p. 4. However, after recognizing explicitly "the potential to carry out collaborative research in this area," the reviewers made the apparently contradictory statement: "However, the lack of direct experience of any of the researchers with nitrite studies and the lack of publications dealing with nitrites does detract from the likelihood of success of the proposed project." We shall deal with this reservation and others in the next section.

Duesberg's application was supported, among others, by Science editor Daniel E. Koshland, who wrote directly to the Study Section of the National Institute on Drug Abuse on 26 August 1993. Koshland stated: "As an observer, I have in the past been critical of Duesberg for not suggesting experiments to resolve this controversy. However, he has now answered my call with a proposal to test the role of nitrite inhalants as a cofactor in AIDS. Certainly this idea seems intuitively to have merit, as nitrites have long been known for their proven mutagenic and carcinogenic effects. He plans to extend some unfinished work by other laboratories in the mid-1980's on mice, examining the physiological and immunological effects of long-term (six months or more) exposure to volatile nitrites."

Koshland added that "while the early research yielded promising results, including evidence of immunotoxicity, it was never properly confirmed or followed up. Duesberg's proposal is a specific, workable one that will be done in collaboration with an inhalation toxicologist at the University of California, Davis." Koshland also commented more generally that "given the critical information that would be generated by such a study, regardless of its outcome, I believe the time has come for this experiment to be performed."

2. Non-funding of the Duesberg-Raabe Proposal

In December 1993, Duesberg received notice that his application would not be funded. The boxed official statement to this effect was:

The scientific merit review of your application (1R01oA/AI0a3391-01) is complete. The Initial Review Group (IRG) has recommended that NO FURTHER CONSIDERATION BE GIVEN TO THIS APPLICATION. Applications so designated cannot be funded in their current form; therefore, they are not routinely scheduled for second level review by the National Advisory Council/Board. An IRG summary statement containing important evaluative comments will automatically be sent to you in approximately 8 weeks. Until then, no specific information regarding the review will be available. However, you may call the contact number above at any time with other questions. After receiving your summary statement you may also call to discuss the contents, and for advice regarding a possible re-submission. If you submit a revised application, you must follow the instructions in the application form and respond especially to comments in the summary statement.

Thus the proposal did not even receive a "priority score," or a full review, but was summarily rejected at the initial stage.

The "Summary Statement" rejecting the proposal contained several objections:

- One objection was that "the proposal does not describe any preliminary studies," although the Summary Statement recognized that "the preliminary studies section describes experiments performed by other groups that should be in the background and significance section." Indeed, the proposal described systematically many preliminary studies by other groups. Why it should be a cause for rejection that Duesberg's lab did not do preliminary studies when others have done them is beyond me, and I regard this reason as illegitimate. It is now for the community of scientists to evaluate the legitimacy of this reason. Aside from that, the Duesberg lab does not have the money to make preliminary studies, so it's caught in a Catch 22 situation even if one accepts (which I do not) the legitimacy of the objection (universally? in some specific case? in the present case?).

- Another objection is that some studies indicate that certain concentrations of amyl nitrite proposed in the Duesberg proposal are too low to cause immunodeficiency in mice, and thus "may not produce meaningful results since this dose was not immunotoxic in several studies." However, the proposal did propose to vary the concentration of amyl nitrite, starting with low doses and increasing the doses in an attempt to determine threshholds of toxicity, so the objection is simply invalid.

- A third objection was that only a "onesided rationale" was presented for the proposal. "A more thorough and balanced description of the pertinent literature would instill more confidence in the rationale and design of the proposed studies." I regard this objection as invalid. The proposal took place in a well-known history of AIDS, when others, including those who contributed to NIDA's research monograph "Health Hazards of Nitrite Inhalants" had found results compatible or even supporting the nitrite-AIDS hypothesis. Such results need to be complemented by further experiments instead of being discouraged. It was not Duesberg's responsibility to present a many-sided rationale for doing the proposed experiment. The experiment was designed for a specific purpose, and would add knowledge complementary to other available results. Let the experiment be made, and we'll see what comes out.

- It was claimed that "the proposed design of the mouse experiments is not clear," because of the order in which inhalants would be given after mice being exposed to virus. But the proposal would give mice simultaneously virus and inhalants, and see how they progress together to test inhalants as a "cofactor." The proposal would also give inhalants alone. Of course, other experiments could be done in giving inhalants frst, giving virus first, or whatnot. Just because there are several variations which could give rise to several types of experiments is not a justification to prevent one among many possible experiment from being carried out.

- The last objection was the period of 6-24 months exposures for mice. The objection states: "Twenty-four months is a very large part of the total life span of laboratory mice. Many mice may not survive the experiment." But results would already have been obtained for exposures of 6 months, and pushing the exposures to 24 months would not invalidate the results for 6 months, so the logic of the objection is defective. In addition, cancer studies on mice which routinely study mice for periods up to 24 months are routinely funded. Therefore recommending that the proposal not be funded partly because the period exposure for mice goes up to 24 months is an illegitimate recommendation.

3. Journalistic Treatment of the Case by Science

In his letter to the National Institute on Drug Abuse, Koshland recognized the scientific and public interest of the proposed experiments. He wrote explicitly: "I believe that this research would add much to our understanding of AIDS, and I have told Duesberg that I would consider such data important material for readers of Science if it develops appropriately."

As of now, the material can't develop because it is obstructed by the National Institute on Drug Abuse and its referees.

Not having seen any report on these matters in Science, I contacted Science's news editor Ellis Rubinstein. In a letter dated 19 January 1994, I informed him of the above events. I thought that the difficulties Duesberg was experiencing document an important case when someone wants to do an experiment which might raise questions about the current prevalent dogma on HIV and AIDS, but cannot get funded. I added the comment that an appropriate news report in Science about these events would be especially relevant because Science's own editor urged the funding.

Following my letter, Science reporter Jon Cohen contacted Duesberg on the phone, and also wrote him on 8 February that he was interested in doing a story about the rejected grant proposal. Jon Cohen stated: "The main question I have is this: Are the reviewers' criticisms unjustified?...Any story I might do I'm sure would hinge on that question." In response, Duesberg submitted the names of four toxicologists whom Cohen might contact to get their views.

On 21 March 1994, Jon Cohen wrote back to Duesberg that he contacted six "researchers" about the grant proposal, and that three wrote back. Cohen enclosed their signed comments. Cohen also stated that two others told him verbally of "problems" they had with the proposal, and the sixth did not reply. According to Duesberg, Cohen gave him the names of all six (including Gallo, who was one of the two expressing his "problems" only verbally). Four out of the six were retrovirologists. Duesberg commented that he would consider "none of these retrovirologists appropriate for reviewing a toxicology proposal such as "the one he presented. Duesberg's list of four toxicologists was recommended to him by Harry Haverkos or by Otto Raabe. Cohen chose only one of them. In any case, the "researchers" consulted by Cohen effectively became reviewers for Science.

On the basis of the reviews he got, Cohen wrote to Duesberg that he "did not see a story for Science about the NIH not funding" the proposal. Cohen's letter to Duesberg was under a SCIENCE letterhead.

The comments of the one "researcher" who had been recommended by Duesberg, say Reviewer R1, were mostly favorable, although mentioning "deficiencies in detail." As mentioned previously, Reviewer R1 is a toxicologist. The overall conclusion from reviewer R1 was as follows:

Reviewer R1. Conclusions. I think it is important that NE be tested for carcinogenicity in animals with and without infection with a retrovirus. I think the investigators could perform these tests if they did some preliminary studies and if they first answered the criticisms in a future revised application. Hence, I think a revision of the grant could well be fundable. I consider that a judgement of "not recommended for further consideration" is harsh and unfair, and is partly based on wrong premises as noted above. This judgement may indeed prevent a useful research project from being carried out. I disagree with most of the views of Dr. Duesberg about the causes of AIDS, but hope that he is sufficient of an objective scientist to perform the tests properly (if he revises the application and does some preliminary studies) and hope that he will report the results promptly whether or not they support his views. (He does state that he will report the results whichever way they turn out.)

The other two "researchers" who wrote back were not among those suggested by Duesberg. One of them was extremely unfavorable. I quote from what he wrote to Jon Cohen.

Reviewer R2. I must assume that the average quality of NIMD grants is as high as those funded by NIAID. On this assumption, if I submitted an application of this standard to NIAID, I would not expect it to be funded. The overall content is very meager. Firstly, the background section is strongly biased toward a particular hypothesis and either ignores or minimally discusses contrary views...

Kaposi's sarcoma is a focus of this application. There is reasonable, but not overwhelming evidence for an infectious agent other than HIV that causes KS. The pathogenic effects of such a microbe may be facilitated by HIV-induced immunosuppression, and it is possible that HIV may also promote the development of KS directly. Oral-fecal contact has been linked with later KS development, perhaps due to microbe transmission, and such sexual activities may be associated with nitrite usage. But there is no compelling evidence that KS, or AIDS, is caused by nitrite usage per se,,.

...But is this proposal going to prove that nitrites cause AIDS or AIDS-defining illnesses such as KS? I very much doubt it...dosing mice chronically with compounds does not prove that the same conditions will be found during "normal" human usage. The toxicological limitations of the experiments have been pointed out by the study section; I am not qualified to assess the validity of the objections, but they seem reasonable...

In short, this proposal suffers from a poorly justified hypothesis, a shortage of preliminary data and a very sketchy set of experimental proposals that would never in themselves achieve the aim of proving nitrite usage to cause AIDS...I am convinced that the study section has reviewed the grant application appropriately and professionally...

Reviewer R2 also made extremely strong comments against Koshland's letter supporting Duesberg's grant application, and the propriety of such support. Short of reproducing both letters in full, which I cannot do for a number of reasons, I do not want to quote from those comments because readers would not have the full context for these comments (that is both Koshland's letter and Reviewer R2's full comments) to verify their legitimacy.

The third review shuffled back and forth. Excerpts from it will give its gist.

Reviewer R3. I agree with Dr. Koshland's letter that Duesberg should have an opportunity to experimentally defend his proposal that nitrite inhalants are important factors (or co-factors) in immunosuppression, K.S. and/or AIDS. I am not sure that without some preliminary data from his lab, as well as evidence that the collaboration set up with Otto Raabe is workable, that the application is worthy of funding. The Study Section Summary Statement also correctly notes that the design of the mouse experiments is not clear. Based on these considerations, I think that Peter himself as a reviewer would not support what might be considered as a "fishing expedition."

On the other hand, some of the points in the grant application are noteworthy of study, e.g., determining appropriate doses of nitrite inhalants in mice that can be validly used to study their immunotoxic potential. However, I am not a toxicologist and would defer to such expertise on this point, as well as on which nitrite derivatives are best to utilize.

In summary, Duesberg raises a highly relevant and important set of experiments that he and his group have the capability to perform; however, the lack of preliminary data and clear rationale would generate only moderate enthusiasm for funding at this time. On the specific issue of whether the application should have been "not recommended for further consideration" (NERF), that is a judgement call. I would not have gone that far based on my limited reading of the proposal; however, if I were present at the actual review, listening to the primary and secondary reviewers, there might have been enough concerns raised that I may have supported the NERF view.

4. Some Comments

I shall comment on statements by Reviewers R2 and R3. These comments merely give a sample of my objections to their evaluations.

(a) Reviewer R2 asserts: "Firstly, the background section is strongly biased toward a particular hypothesis and either ignores or minimally discusses other views." So what? It is not the responsibility of the proposal to discuss other views in a major way. The point of the experiments is to test some aspects of the particular drug hypothesis. However, it is important that other hypotheses were not disregarded in the proposal, because the experiments would be conducted on control groups of mice some of which would be infected with Molony leukemia virus and some of which would not. This virus is claimed to cause mouse AIDS.

(b) Reviewer R2 asserts: "But there is no compelling evidence that KS, or AIDS, is caused by nitrite usage per se." So what? In the statement preceding this assertion, Reviewer R2 accepted that "there is reasonable, but not overwhelming evidence for another infectious agent other than HIV that causes KS." So according to Reviewer R2 the evidence that KS is caused by HIV is also not compelling. Is this a reason not to perform further experiments to test the extent to which HIV does or does not cause KS or AIDS? The medical establishment has tried for a decade to determine the pathogenesis of HIV, without success. The people who support the HIV-AIDS hypothesis have only epidemiological evidence (for whatever it's worth), which is not compelling.

There is also no compelling evidence that KS, or AIDS, are not caused by nitrite usage per se. If there was compelling evidence that nitrite use causes KS or AIDS, there would be no need to do experiments about it.(3) Conversely, preventing such experiments from being performed prevents evidence, compelling or otherwise, to develop one way or the other. As a scientist, I object to the a priori obstruction placed in the way of experiments to investigate the possibility that nitrite usage per se may cause KS or AIDS.

(c) Reviewer R2 asks the question: "But is this proposal going to prove that nitrites cause AIDS or AIDS defining illnesses such as KS?" and asserts: "I very much doubt it." Indeed, the proposal makes no claim as to what it's going to prove. One cannot determine what a proposal is "going to prove" before having made the experiments. The experiments themselves could have inconclusive results, for various reasons, thus not "proving" anything except that a certain set of results is inconclusive. Even if all experiments eventually show a uniformity that after taking poppers in sufficient quantity for a sufficiently long period, mice develop immunodeficiencies or cancer type diseases, the experiments still would not "prove that nitrites cause AIDS" in human beings when taken in sufficient quantities for a sufficiently long period (possibly not the same period as for mice). Thus, speaking for myself, I don't "very much doubt" that the experiments "will prove that nitrites cause AIDS or AIDS related diseases." I know they will "prove" no such thing, defectively formulated in such absolute generality by Reviewer R2.

However, the experiments might suggest others; they might be preliminaries for further experiments, on other animals, varying circumstances or whatever. That's what experiments are for, to test various ranges of validity of various hypotheses. If the experiments systematically show the above uniformity, they might also open some people's minds to consider more seriously the possibility (not certainty) that nitrites may cause AIDS related diseases in human beings. Conversely, if they turn out inconclusive or show an opposite uniformity, they might have the opposite effect. The effect of the experiments will depend on how they turn out, it will be different on different people, and it cannot be predicted in advance, partly because it will depend on many factors in many ways.

If a reviewer's doubts that Duesberg's proposal will prove that nitrites cause KS or AIDS were taken as a reason not to fund the proposal, and as a reason not to report the matter in Science, then I object and I ask the scientific community to evaluate the legitimacy of non-funding and non-reporting based on such a reason.

I add one comment about the third review, concerning the nature of scientific research.

Reviewer R3 writes: "Based on these considerations, I think that Peter himself as a reviewer would not support what might be considered as a 'fishing expedition'." I have several objections to this sentence. First, I find it illegitimate to presume what "Peter" would do, especially since Duesberg made the proposal for the experiments in the first place.

More fundamentally, I object to such a put-down of "fishing expeditions" in the scientific context, with the innuendo contained in the term "fishing expeditions," which has been used commonly in other contexts. A "fishing expedition" in the scientific context is quite different from a political context when some parts of a political establishment go on a "fishing expedition" against people with a different political opinion. I think "fishing expeditions" against the great mysteries of nature are the essence of original scientific research. I agree with Koshland that the material of Duesberg's experiments would be of great interest for readers of Science if, as Koshland writes, "this material develops appropriately"; and I think the material would be of great interest to other scientists and to the public as well. Having the material in Science (if it develops appropriately) would be just a start. But we can't know how the material will develop if the development is obstructed a priori by funding agencies.

5. A NIDA Meeting on Nitrite Inhalants

On 23-24 May 1994, the National Institute for Drug Abuse (NIDA) sponsored a meeting to discuss "the role of nitrite inhalents in AIDS, particularly in its most visible expression, Kaposi's sarcoma." This meeting was reported in the article "NIH reconsiders nitrites' link to AIDS" (Biotechnology, 12 August 1994, p. 762). I have given an account of this article elsewhere at greater length ("HIV and AIDS: Questions of Scientific and Journalistic Responsibility," Yale Scientific November 1994), but it is relevant to report here an about-face by Gallo. The Biotechnology article stated:

Finally, Robert Gallo of the National Institutes of Health (NIH, Bethesda, MD) surprised some attendees and panelists by arguing that HIV is not the primary cause of KS [Kaposi's Sarcoma], although it may aggravate the condition once KS is caused by "something else." As to what that something else might be, Gallo favored a microbe that has yet to be discovered, though he allowed that carcinogenic nitrites could well be a primary cause. In the true spirit of scientific inquiry, quite different from the rancor of prior discussions of alternative causes of AIDS, Gallo called for funding of Duesberg's nitrite experiments."

Question: Did Gallo inform Science and Jon Cohen of his changed position about the funding of Duesberg's nitrite experiments? Do the editors of Science and its reporters read Biotechnology? I sent them a copy of the above article when it appeared,(4) In addition, Koshland wrote another letter on 24 August 1994, iterating his support of funding for Duesberg's experiments.

6. Developments in Fall 1994

The first version of the present article was sent to editors of Science in spring 1994, among many others on the "cc list." In September 1994, I had a major mailing containing an updated version, together with my article on "HIV and AIDS... " Both were then accepted for publication by the Yale Scientific, with the "HIV and AIDS..." article to appear in November, while the "funding" article would appear in the next issue, January 1995. Science editors and reporters again were on the mailing list for my September mailing to about 100 people. With these mailings I was attempting to fill the information vacuum which resulted from Jon Cohen informing Duesberg under a "SCIENCE" letterhead that he did "not see a story for Science about NIH not funding" Duesberg's proposal. I was also attempting to put pressure on Science to report various events.

In October 1994, Jon Cohen asked Duesberg for an interview to be used in an article for Science. Duesberg accepted, provided Cohen's questions were put first in writing. Duesberg would then also answer in writing, and Duesberg accepted having a verbal exchange afterwards. All of these took place. Cohen submitted a first batch of questions 10 single-space pages long, which Duesberg answered point by point in 11 single-space pages. Cohen submitted a second batch of questions again 10 single-space pages long, which Duesberg answered in 7 single-space pages. The subsequent verbal exchange was several hours long.

Duesberg had some objections to the way Cohen's questions were put together, since they all assumed implicitly that HIV is the cause of AIDS. The questions prejudiced the issue toward the HIV causality. To a large extent, Cohen was asking Duesberg to comment on some scientific articles purporting to show or to support the causal relation of HIV and AIDS. The questions were detailed and specialized. Duesberg found that most of the points raised by Cohen were in effect already answered in two papers of his ("AIDS acquired by drug consumption and other noncontagious risk factors," Pharmacology & Therapeutics 55: 201-277; and "Human immunodeficiency virus and acquired immunodeficiency syndrome: Correlation but not causation," Proc. Natl. Acad. Sci. USA 86: 755-764). In these papers, among other things, Duesberg cited much scientific literature, but he did not and could not cite the entire literature. However, Duesberg claimed that the articles he cited were typical, and he analyzed many common defects in the current literature about HIV and AIDS. Cf. Appendix 1 below, which reproduces a list of the specific objections to certain scientific articles noted by Duesberg in a letter to Cohen dated 20 October 1994.

Cohen also asked why Duesberg had not cited other articles which Cohen submitted for his consideration. In fact, some of the articles brought up by Cohen had not appeared at the time of publication of the Pharmac. Ther. and PNAS papers cited above. The defects analyzed by Duesberg in these papers were similar to defects which he found in the articles brought up by Cohen.

My article in the Yale Scientific appeared in the middle of November, and I distributed several hundred copies, including half a dozen copies to various people at Science. After internal consultations and revisions, a final version of Cohen's article appeared in Science, 9 December 1994, under the title "The Duesberg Phenomenon." In this article, Jon Cohen stated: "But because the Duesberg phenomenon has not gone away and may be growing, Science decided this was a good time to examine Duesberg's main claims." Thus Science and Jon Cohen changed their mind between spring 1994 and fall 1994. In this published version, Cohen finally reported Koshland's support as follows: "Also unpersuaded of Duesberg's ideas--but persuaded he shouldn't be shut out of scientific resources--is Daniel Koshland Jr., editor-in-chief of Science, who has written letters to the National Institute on Drug Abuse supporting Duesberg's recent grant proposals."

Nevertheless, as of December 1994, all recent applications by Duesberg for funding of his lab were rejected. This was correctly reported by Cohen, who wrote: "In addition, Duesberg has been turned down by funding agencies on several new proposals to study both AIDS and cancer." Cf. Appendix 2 for a summary of these proposals.

A subsequent article by Jon Cohen in Science 16 December 1994 reported on the possibility of a new virus causing Kaposi's sarcoma (cf. my article "HIV and AIDS .... " 6). In a letter to the editors sent 4 January 1995, Duesberg stated:

Science wonders (16 Dec., p. 1803) about the "mystery" that "KS is almost exclusively confined to male homosexuals..."

1) Since nitrites are some of the best known mutagens and carcinogens (3), I propose the following experiment to solve the "mystery": Expose 100 mice, or cats, or monkeys to nitrite inhalants at doses comparable with human recreational use and for time periods approximating the so-called 10-year latent period between infection by HIV to the onset of AIDS--possibly a euphemism for the time of drug use necessary for AIDS to develop. (It takes 10 to 20 years of smoking for emphysema or lung cancer to develop.) I would predict this result: Immunodeficiency, pneumonia, and pulmonary KS in animals.

2) I also propose to "mainstream AIDS researchers" an easy epidemiological experiment to test my hypothesis that HIV is not the cause of AIDS. According to Science, these researchers argue that it is "impossible" to eliminate confounding factors from HIV in typical AIDS risk groups, as for example in hemophiliacs "because [they] do not keep track of each factor VIII treatment" (9 Dec., p. 1645). Therefore I propose to compare the incidence of AIDS-defining diseases in 3650 homo-or heterosexual American men, who are not on transfusions and recreational drugs or AZT, but are HIV-positive, to the incidence in 3650 HIV-negative counterparts. These healthy subjects could be found by the U.S. Army, which tests over 2.5 million per year, or among those contributing to the blood banks, which test over 12 million a year. If the 3650-day latent period is correct, every 2 days one of the people that are HIV positive would develop AIDS. I would predict this result: The percentage incidence in the HIV-positive group will be the same as in the HIV-negative group.

If the mainstream AIDS researchers are not already doing these experiments, I would be delighted to do them provided I could get funded.

At the time this article goes in production, Duesberg was not funded.

The scientific community is entitled to know of the events I have reported above, both concerning the non-funding by NIH and the circumstances under which Science reports or does not report events.

References

[CDC 1983] Reports on AIDS, Morbidity and Mortality Weekly Report, 9 September 1983, 457-8, 464 ; compiled in a collection of such reports, 1981-1986, p. 44

[CDC 1985] Revision of the case definition of acquired immunodeficiency syndrome for national reporting--United States, Morbid. Mortal. Week. Rep., (1985) 34, pp. 373-375

[F&F 1990] E. FEE and D. FOX, AIDS--The Making of a Chronic Disease, U of C Press, 1990

[HAV 1988] Harry Haverkos, Kaposi's Sarcoma and Nitrite inhalants, Psychological Neuropsychiatric, and Substance Abuse Aspects of AIDS, edited by T. Peter Bridge et al., Raven Press, New York (1988) pp. 165-172

[NIDA 1988] Health Hazards of Nitrite Inhalants, edited by Harry Haverkos and John Dougherty, HHS Public Health Services, NIDA, 5600 Fishers Lane, Rockville MD 20857

Appendix 1. Excerpt from a Letter from Peter Duesberg to Science Reporter Jon Cohen October 20, 1994

The results in the HIV-AIDS papers, on which you ask me to comment and which form the basis of your questions, are entirely similar to the results in papers I cited in my articles, and they suffer from similar defects. The defects of these HIV-AIDS papers include:

(1) discarding a priori other possible causes of AIDS (whatever it is) besides HIV;

(2) not measuring lifetime use of foreign proteins transfused or of drugs consumed in AIDS risk groups and patients;

(3) not comparing morbidity and mortality of HIV-positive drug users, transfusion recipients and other risk groups to matched HIV-negatives;

(4) obscuring the role of certain factors, notably drugs and foreign proteins, by averaging certain results for people who may have used drugs only a short time, with those who have used drugs for a decade or more;

(5) failure to determine annual AIDS risks of HIV-positive persons of different risk groups and countries. Instead cumulative AIDS statistics are reported, and these always go up;

(6) failure to determine whether outside the known AIDS risk groups, AIDS has increased mortality and morbidity of the general population in any country, or whether it is a new name for the normal background of these diseases. This is a consequence of not comparing the morbidity and mortality of HIV-positives to HIV-negatives in the general population. For example, the rare coincidence of HIV and pneumonia in persons of the general populations must be shown to exceed the normal background of AIDS-defining diseases in a given risk group before it can be considered evidence for HIV causing AIDS;

(7) failure to consider that all AIDS-defining diseases are previously known diseases that occur at a low rate in all people and at a higher rate in AIDS risk groups;

(8) using the circular AIDS definition. That is to report AIDS-defining diseases in HIV-positives as AIDS, and either not to report clinically diagnosed AIDS diseases in HIV-negatives or not to report controls at all;

(9) failure to recognize that "AIDS tests" detect antiviral immunity which is a prognosis against rather than for an HIV-disease, if such a disease exists;

(10) failure to distinguish between infectious and thus potentially pathogenic HIV, and DNA or RNA of latent HIV, or even antiviral antibodies which have no known pathogenic potential;

(11) failure to account for the unpredictable latent periods from HIV infection to AIDS, that are claimed to range from 10 months to over 10 years. These long latent periods are totally incompatible with the short generation time of HIV, which is only 24 to 48 hrs;

(12) complete refusal to consider the simplest and most plausible HIV hypothesis- namely that HIV is a harmless passenger virus. The criteria of a passenger virus: (i) the time of infection is irrelevant to the onset of disease; (ii) the passenger virus can be either active or passive during the course of the disease; (iii) the passenger virus can be completely absent during the disease. HIV meets all criteria of a passenger in AIDS perfectly;

(13) failure to report the toxicity and lifetime dosage of antiviral drugs like AZT, and failure to report AZT compensating, lifesaving treatments like transfusions.

Appendix 2. List of Rejected Grant Applications by Duesberg

[I reproduce below excerpts from a letter dated 6 December 1994, which Duesberg wrote to me. I had no further time to look into the references and letters he gave me accompanying his summary, the way I looked previously into the reports from the reviewers for Jon Cohen. S.L.]

CANCER GRANTS

1) In 1990, the competing renewal of my Outstanding Investigator Grant (OIG), "Retroviral onc genes and cellular proto-onc genes" was turned down. This type of grant had been awarded in 1985 to only about a dozen outstanding scientists for a 7 year term. My grant resulted in 86 publications, including research papers, theoretical papers, reviews and reports during its term period.

The pink sheet of the mail ballot review of this renewal application said in Oct. 1990: "... his productivity has been a bit lower and his science, although still solid, is not as sharp and imaginative as before.," "... much of the investigator's time and effort during the past period has been occupied by theoretical issues pertinent to his research and other interests." (copy enclosed)

This decision was appealed on two grounds: 1) Three of the reviewers listed on the pink sheet as having participated in the review never reviewed the application .... 2) At least two reviewers had personal and commercial conflicts of interest... After a lengthy correspondence with the NIH and the administration of UC Berkeley, UCB signed a rare appeal to the NIH in March 1992 to re-review my application. This appeal was granted in the spring of 1993 (see letter by Dr. Blair from the NIH).

2) In May 1993 my appeal of the OIG review was turned down by the Experimental Virology Study Section of the NIH with a nonfundable priority: "Applicant whose productivity has recently diminished both in quantity and most disturbingly in quality...a vast amount of highly relevant work from other laboratories is neither acknowledged nor incorporated into the proposal" (pink sheet enclosed).

3) In May 1993 an application to the Tobbaco-Related Disease Research Program (TRDR) of the University of California, entitled "The role of chromosome abnormalities in cancer" was accepted but with the priority score of only 8% (letter enclosed).

4) In May 1994 a revised application to the same TRDRP again entitled "The role of chromosome abnormalities in cancer" was rejected with the nonfundable priority "Not recommended for further consideration" (letter enclosed).

5) In July 1994, a revised application entitled "The role of chromosome abnormalities in cancer" was ranked in the bottom 10% by the American Cancer Society and was not approved for funding (letter enclosed).

6) In December 1992 a postdoctoral grant application was submitted to the Cancer Research Coordinating Committee of the University of California entitled "The role of chromosome abnormalities in cancer." The application was not funded according to a letter from May 1993 (enclosed).

7) In December 1993, a postdoctoral grant application was submitted to the Cancer Research Coordinating Committee of the University of California entitled "Cancer caused by chromosome abnormalities?" The application was not funded according to a letter from May 1994 (enclosed).

8) In December 1994 a new postdoctoral grant application was submitted to the Cancer Research Coordinating Committee of the University of Calffomia entitled "The role of chromosome imbalance in cancer."

AIDS GRANTS

9) In February 1993 a grant application was made to the Universitywide Aids Research Program of the University of California entitled "Animal test of the hypothesis that amyl nitrites cause AIDS." The application was ranked "within the fourth quartile." With regard to its approval a split vote with five for and four against was reported (see enclosed letter).

10) In August 1993 an application was made to the National Institute of Drug Abuse (NIDA) entitled "Animal tests of the AIDS risks of nitrite inhalants." The application was accompanied by an endorsement from Dan Koshland, editor of Science. The application was "not recommended for further consideration" in a letter from the NIDA of January 1994 (enclosed).

11) In August 1994 a revised application was made to the National Institute of Drug Abuse entitled again "Animal tests of the AIDS risks of nitrite inhalants." The application was accompanied by an endorsement from Dan Koshland, editor of Science. Today I received a letter dated November 30, 1994, that the initial review group has recommended again "NO FURTHER CONSIDERATION BE GIVEN TO THIS APPLICATION (enclosed)."


Updated 5 January 1995. Reprinted updated in the collection: AIDS: Virus- or Drug Induced?, P. Duesberg, editor, Kluwer Academic Publishers (1996), pp. 297-307

Footnotes

1. According to [HAV 1988], p. 165: "Nitrite inhalants were investigated as a possible cause of AIDS early in the epidemic, partly because of the preponderance of homosexual men who used nitrites among the early patients with AIDS..."

"In 1981, CDC initiated surveillance in the United States for patients under age 60 with KS and opportunistic infections... The initial CDC definition of AIDS did not require immunologic studies or testing for any possible viral causes, nor did it exclude patients with normal immunologic results (34)."

Some experiments were made at that time, and were mentioned in a report on AIDS by the Center for Disease Control [CDC 1983] (p. 44). The CDC concluded that "although the data obtained in this study indicate that IBN was not immunotoxic for mice, these drugs do have toxic effects... Reported side effects include: dizziness, headache, tachycardia, syncope, hypotension, and increased intraocular pressure;... Nitrite inhalants do not appear to be implicated as a cause of the immunosuppression seen in AIDS, but their role as a cofactor in some of the illnesses found in this syndrome has not been ruled out." One effect of the CDC taking this position was to influence others not to do further experiments in the direction of the nitrites-AIDS hypothesis.

In 1985, according to that same article by Haverkos: "Following the identification of human immunodeflciency virus (HIV) as the cause of AIDS, CDC changed the definition of AIDS to include HIV serology testing as part of the definition..." [CDC 1985]

The book AIDS--The Making of a Chronic Disease [F&F 1990] contains an article by Gerald Oppenheimer, giving a history of the early days when the nitrite-AIDS hypothesis was considered seriously, and studies were made on groups of homosexual or bisexual men, who were found to use drugs, especially nitrites, extensively. See especially pp. 57-60. Later in his article, Oppenheimer considers the history of the HIV-AIDS hypothesis, and concludes (p. 75): "The history of the epidemic demonstrates that the construction of HIV infection was and is a dynamic process in which different scientific specialities negotiated definitions that, to a degree, reflected their relative power."

2. Titles of the sections: Nitrite inhalants: Historical Perspective; The Fate and Toxicity of Butyl Nitrites; The Acute Toxicity of Nitrite Inhalants; Indications From Animal and Chemical Experiments of a Carcinogenic Role for Isobutyl Nitrite; Toxicity of Inhaled Isobutyl Nitrite in Balb/c Mice: Systemic and Immunotoxic Studies; Altered T-Cell Helper/Suppressor Ratio in Mice Chronically Exposed to Amyl Nitrite; Effects of Nitrites on the Immune System of Humans; Deliberate Inhalation of Isobutyl Nitrite During Adolescence: A Descriptive Study; Nitrite Inhalants: Contemporary Pattems of Abuse; Epidemiologic Studies---Kaposi's Sarcoma Vs. Opportunistic Infections Among Homosexual Men With AIDS.

3. The need for such experiments was explicitly recognized in NIDA's "Summary Statement," which I have already quoted to the effect that "the major strength of this proposal is that it addresses the important public health problems of whether nitrite abuse acts as a cofactor in AIDS pathogenesis and if nitrites can cause Kaposi's sarcoma in the absence of retrovirus infection."

4. Actually, this statement of Gallo was subsequently nullified. In an interview with The Scientist (14 November 1994), answering a question whether the Biotechnology article was *accurately reporting his views," Gallo said: "They were. But listen carefully. The proposal that Duesberg made in front of me at a Kaposi's sarcoma [KS] meeting that was organized by the popper people I thought was a reasonable idea. But that doesn't mean that I saw the thing written up and that it was written up properly." The Scientist interview with Gallo on 14 November was published along with an article on an AIDS conference celebrating Gallo's lab. The article was entitled: "Gallo's Meeting: A Scientific Folk Festival." These two items (article and interview) exist as part of the record. I found both exceedingly tendentious, and suppressive of much information which would give a quite different aspect to the questions covered by these two pieces, but here is not the place to document the tendentious and defective journalism of The Scientist.


VIRUSMYTH HOMEPAGE