Duesberg and the Right of Reply
According to Maddox-Nature
Peter H. Duesberg and Harvey Bialy*

Genetica Monograph "AIDS: Virus- or Drug-Induced?" 1995.
Kluwer Academic Publishers, Dordrecht, The Netherlands.

In 1993 John Maddox, the editor of Nature, commissioned a commentary refuting the hypothesis that drugs cause AIDS (Ascher et al., 1993). The piece described 215 patients each of which had used drugs (Duesberg, 1993a; Duesberg, 1993b; Duesberg, 1993c). In view of this Duesberg sent a letter to Nature arguing that the perfect correlation between drug use and AIDS confirmed, rather than refuted, the drug hypothesis. Maddox censored the letter and wrote an editorial "Has Duesberg a Right of Reply?" (Maddox, 1993). The editorial pointed out that the world's oldest science journal could not afford an open scientific debate on the cause of AIDS because of the perceived dangers of infectious AIDS.

In an editorial on January 19, 1995, Maddox promised to lift the censorship to give "Duesberg and his associates an opportunity to comment" on two Nature studies that in his opinion prove the HIV-AIDS hypothesis.

In the following we document how Maddox-Nature honors its commitments. Our documentation includes:

(i) A photocopy of Maddox' News and Views article of January 19, 1995,

(ii) A summary of a phone conversation between Maddox and Bialy,

(iii) Our letter to Maddox answering his invitation,

(iv) Our commentary on the two new Nature studies,

(v) Maddox' response to our commentary,

(vi) Our response to Maddox,

(vii) What Nature published from and about Duesberg and Bialy on May 18, 1995,

(viii) Nature's final letter.

References:

Ascher, M. S., H. W. Sheppard, W. Winkelstein Jr., and E. Vittinghoff, 1993. Does drug use cause AIDS? Nature (London) 362: 103-104.

Duesberg, P., 1993a. Aetiology of AIDS. Lancet 341: 1544.

Duesberg, P., 1993b. HIV and the aetiology of AIDS. Lancet 341: 957-958.

Duesberg, P. H., 1993c. Can epidemiology determine whether drugs or HIV cause AIDS? AIDS-Forschung 12: 627-635.

Maddox, J., 1993. Has Duesberg a right of reply? Nature (London) 363: 109.

This journal has offered Dr. Peter Duesberg and his associates an opportunity to comment on last week's publications suggesting that the immune system reacts hyperactively to HIV infection.

The publication last week of two important articles on the dynamics of the infection of people by HIV is agreed to have been a important landmark in the process of understanding the disease called AIDS, but not everybody will be aware of that. Reporting of the event has been curiously selective. In particular, the British newspaper The Sunday Times, which as recently as a year ago was replete with accounts of how HIV can have little or nothing to do with the causation of AIDS, chose not even to mention the new developments in last Sunday's edition.

Is it planning a major account of how it came to be so misled, thus to mislead its readers? Or is it waiting for a sign from Professor Peter Duesberg, of Berkeley, California, who started the hare the newspaper followed eagerly for two years?

The reasons why the new developments are (or should be) an embarrassment for Duesberg are simply put. Almost from the outset of AIDS as a recognized disease in the early 1980s, the objective index of an infected person's state of health has been the concentration in the blood of T lymphocytes carrying the CD4 antigen. The more advanced the infection, the smaller the concentration of CD4+ cells.

But Duesberg was quick to point to a paradox in the observations: although the concentration of CD4+ cells might decline with the persistence of infection, there was no dramatic increase of the frequency of infected T cells as infection gave way to overt disease. Cell death by inter-cellular infection could hardly be consistent with that state of affairs.

In essence, the new developments resolve the paradox by showing that the T cells in an infected person's blood are likely to have been created only in the few days previously. There will not have been time enough for more than a small proportion of them to have become infected, while those that harbour virus will be killed off very soon. So the scarcity of T cells from which virus can be recovered in test-tube experiments is consistent with the assertion that the immune system is in overdrive from the onset of infection by HIV.

On this (new) view, the progressive decline of the CD4+ concentration with the duration of infection is rather a symptom of the underlying infection than the crux of its mechanism. What seems to matter is that there should be cells (including T cells) somewhere in the body (the lymph nodes are likely candidates) from which virus particles continue to leak into the blood plasma. In other words, Duesberg is right to have argued all along that the usually slow decline of CD4+ cells is not consistent with what one would expect from a specific cytotoxic viral mechanism. The explanation is that the CD4+ population in the blood at any time has been freshly created.

Despite this journal's severe line, some months ago, on Duesberg's right of reply to critics of his position, it is now in the general interest that his and his associates' views on the new developments should be made public. Duesberg was not available to take a single telephone call one day last week, nor able to return it, but one of his associates appeared to welcome the idea of a comment on the articles by Wei et al. and Ho et al. (Nature 373, 117-122 & 123-126; 1995). That will be eagerly awaited and will be published with the usual provisos-that it is not libelous or needlessly rude, that it pertains to the new results and that it should not be longer than it needs to be.

Meanwhile, one important question stands out like a sore thumb: why, after more than a decade of research, has it only now emerged that the response of the immune system to infection by HIV is hyperactivity rather than the opposite? Simon Wain-Hobson, writing in News and Views last week (Nature 373, 102; 1995), remarked that the investigators were able to reach their startling conclusions "by teaming up with mathematicians."

Intuitively, the sharp recovery of CD4+ cells in the first few days after the administration of antiviral drugs pointed to their rapid production by the immune system. But in retrospect the good fortune of the investigators is clear. Only with the advent of highly specific drugs directed against HIV was it possible to cut off viral production so abruptly that the decline in plasma viremia could form the basis for a model of viral production. New techniques for assaying the low levels of virus involved were also necessary; had the drugs been available only a few years earlier, these studies would have been impossible on that account.

In retrospect, the dynamics of the immune system would seem to be central to any consideration of the body's response to infection, by measles virus as well as HIV. And modelling of such processes as the production of lymphocytes (B as well as T cells) in the immune response should be a relatively easy task (compared with, say, the appearance of endless molecular species in the evolution of a molecular cloud).

To be sure, immunologists are no strangers to quantitation in this spirit. And the involvement of mathematicians is simply explained by the authors' desire to be sure that even experts in this area approved of their data analysis. But the rarity of such studies says something depressing about the state of biology, for all its modernity. Despite the explosion in molecular knowledge (including molecular knowledge of viruses), the information to perform this kind of quantitative modelling is almost never available. In this case, the relevant data have emerged only after a decade of intensive research, fuelled by intense public interest in a most unpleasant pathogen. But virology is not the only field in which biology would benefit from more quantitative methods.

What more is to come? Now that the basis for the low CD4+ T-cell count in AIDS patients is clear, further studies of the viral dynamics will be eagerly awaited. How much virus is produced by each productively infected cell? How fast is the virus produced by the lymph nodes? And what is responsible for killing the CD4+ T cells? If these last are indeed being destroyed by the CD8+ cells of the immune system, as Wain-Hobson suggests (and this remains to be seen), it will undoubtedly lend further support to the idea that individuals who are repeatedly exposed to HIV while remaining unaffected are protected by their cytotoxic T lymphocytes (Rowland-Jones et al., Nature Medicine 1, 59-64; 1995).

The search for effective antiviral therapy will also benefit. Already Wei et al. have followed the emergence of mutants resistant to one drug, and studies of others, alone and in combination, will surely follow. Here too, improved quantitation of the size of viral pools in different tissues, and their respective replication rates, will be vital.

What does this mean for basic research on AIDS, the cause eloquently advocated a year ago by Dr. Bernie Fields (Nature 369, 95; 1994)? Wei et al. and Ho et al. have provided the basis for a much more pointed programme of investigation from which, no doubt, a complete picture of the dynamics of this hitherto perplexing disease will emerge. A return to basics seems already to have happened. The prospects of therapy are much more difficult to tell, but has a fuller understanding ever failed to deliver improvements of technique? The danger for the Duesbergs of this world is that they will be left high and dry, championing a cause that will have ever fewer adherents as time passes. Now may be the time for them to recant.

On the afternoon of January 12, [1995] the day the Nature issue containing the Ho and Wei et al. papers appeared, and one day after the press conference announcing these landmark publications, I received a rare telephone call from my colleague, the newly knighted, Sir John Maddox, editor of Nature. The essence of the ensuing conversation is summarized below.

After congratulating John on his recently acquired honorific, I asked to what did I owe the pleasure of his call. He then asked me what I thought of the "HIV-1 dynamics" papers. I replied by thanking him for publishing them, as they were so transparently bad, they would convince any reasonable scientist who had the endurance to read them that the HIV-AIDS hypothesis was absolutely intellectually bankrupt. I also chided him by saying that even Wain-Hobson didn't know what to make of them, judging by his incoherent News & Views piece that accompanied their publication.

To my surprise, his response to these remarks was remarkably devoid of any outrage. We discussed in a cursory manner some of the more obvious criticisms of the papers, such as their lack of controls, and the methodological and biological problems with their estimates of free infectious virus. I also mentioned that I thought it ironic that after years of denying that T cells turned over at the rate of 5% in two days, the HIV-AIDS protagonists were now at last admitting this well known fact. He responded by asking how did I explain the "dramatic increase in T cells after treatment with the protease inhibitor." I replied that this transient, hardly dramatic, increase was also a well known phenomena called lymphocyte trafficking, which occurs in response to many chemical insults.

The conversation then changed direction and John said that he had, without success, been trying to reach Peter (Duesberg) to inform him that he was, in this instance, willing to rescind his previous "refusal of the right of reply" and would welcome a correspondence from Peter (and myself) addressing what we perceived as the shortcomings of Ho and Wei et al. He promised me that if the piece was relevant, succinct and not personally rude, he would publish it "unslagged." When I asked him what this meant, he said that it would be published as received, without prior review and without a response appearing in the same issue. I said "do you mean it will be allowed to generate its own replies?," and he said "yes." I congratulated him on his willingness to open a proper scientific debate, and said I would communicate our conversation to Peter.

I was a bit surprised to see his editorial in the following week's Nature in which he went much further than our conversation in offering the pages of Nature to uncensored debate. I was, however, not surprised to discover, some weeks later, that the response which appears unedited in this issue of Genetica, was deemed "too long by half and too unfocussed" to warrant publication in his own highly esteemed journal.

Letter to John Maddox from Peter Duesberg
and Harvey Bialy

February 7, 1995

Sir John Maddox
Nature, Macmillan Publishing
4 Little Essex St.
London, WC2R 3LF England

Dear John,

As per your invitation, published in News and Views "Duesberg and the new view of HIV," and your invitation to Harvey Bialy over the phone, "to comment on last week's publications" by Wei et al. and Ho et al. we submit "Responding to 'Duesberg and the new view of HIV'" by Duesberg & Bialy. We are delighted that after years of editorials, News & Views, and letters and censored letters we have been invited at last to make our case in our own words.

As you can see, our report meets your criteria of "not libellous or needlessly rude, that it pertains to the new results and that it should not be longer than it needs to be." The length of our commentary is compatible with the results presented in the two papers covering 10 pages, and the challenges delivered by the two accompanying News & Views from you and Wain-Hobson.

We both respect your courage and integrity to undertake an uncensored debate on the HIV-AIDS hypothesis.

Best regards

Peter Duesberg
Harvey Bialy

P.S. A hard copy is in the mail. We can send a disc if that helps.

Responding to "Duesberg and the New View of HIV"
Peter H. Duesberg and Harvey Bialy*

The editor of Nature, John Maddox, has issued a published invitation to "Peter Duesberg and his associates ... to comment" on two new studies by Wei et al.1 and Ho et al.2 that he feels lend strong support to the hypothesis that HIV causes AIDS.3 Maddox credits us for having identified two paradoxes of this hypothesis, (i) "Duesberg was quick to point to a paradox ... [that] there was no dramatic increase of the frequency of infected T-cells as infection gave way to overt disease," and that (ii) "Duesberg is right to have argued all along that the usually slow decline of CD4+ cells [T-cells] is not consistent with ... a specific cytotoxic viral mechanism."3

According to Maddox, "the new developments are (or should be) an embarrassment for Duesberg," because they "resolve the paradox." But we do not see any reason why a scientist should be embarrassed for having pointed out paradoxes in the past, which ever way these paradoxes are subsequently solved. We also object to rhetoric personalizing a scientific debate. However, it is embarrassing that in the name of science clinical, public health, journalistic, and political decisions have been made in the past, based on a hypothesis that-we all agree now-was unproven at that time.

Since the HIV-AIDS hypothesis makes many assumptions that are paradoxical, if not bewildering, for pre-HIV virologists, and since the new studies do not clearly define the HIV hypothesis, we shall first state the hypothesis and then explain why, in light of these "new" studies, it remains paradoxical.

In 1984 it was proposed that the retrovirus HIV can cause such diametrically different diseases as Kaposi's sarcoma, pneumonia, dementia, diarrhea, and weight loss.4,5 All of these diseases and over two dozen more are now collectively called acquired immunodeficiency syndrome (AIDS)6 if antibody to HIV is present. But many of these diseases, including Kaposi's sarcoma, lymphoma, dementia and weight loss, are neither consequences of, nor consistently associated with immunodeficiency.7,8 For example Kaposi's sarcoma and dementia have been diagnosed in male homosexuals whose immune systems were normal.9-13 As a cause of these diseases HIV was proposed to follow an entirely unprecedented course of action:

1) HIV was proposed to cause immunodeficiency by killing T-cells. But retroviruses do not kill cells.14,15

2) Within weeks after infection, HIV would reach moderate to high titers of 10-104 infectious units per ml blood,16 sufficient to induce antiviral immunity and antibodies (a positive "AIDS-test"). According to Shaw, Ho and their collaborators, HIV activity is "rapidly and effectively limited" by this antiviral activity.17,18 Prior to antiviral immunity, HIV would neither kill T-cells nor cause AIDS.16,19 But all other viruses are primarily pathogenic prior to immunity; the reason vaccination protects against disease. Not one virus exists that causes diseases only after it is neutralized by antiviral immunity.20,21

3) On average 10 years after HIV is neutralized, the virus is postulated to cause AIDS diseases.5,22 But all other viruses typically cause disease within days or weeks after infection, because they replicate exponentially with generation times of 8 to 48 hours.20,23,24

4) As a consequence of antiviral immunity, the virus titer is typically undetectably low prior to and even during AIDS.25-29 Only in rare cases HIV titers are as high as in the asymptomatic, primary infection.16,30 But in all other viral diseases the virus titer is maximally high when viruses cause disease.20,21

5) Antiviral immunity would typically restrict HIV-infected lymphocytes to less than 1 in 500-prior to and even during AIDS.14,26,27,30-32 But all other viruses infect more cells than the host can spare or regenerate when they cause disease.20,21

6) The hypothesis fails to shed any light on the causation of non-immunodeficiency AIDS diseases, like Kaposi's sarcoma, dementia, lymphoma and weight loss which make up 39% of all American AIDS cases.8,33

Today this HIV-AIDS hypothesis stands unproven and has failed to produce any public health benefits.34-36

The new studies are claimed by two News and Views articles from Maddox3 and Wain-Hobson43 to resolve the paradoxa, (1) how HIV kills T-cells, (2) how HIV causes AIDS, and (3) why HIV needs 10 years to cause AIDS. But we argue that the new studies have failed to resolve any of these paradoxa, in fact they have added new ones:

(1) How HIVkills T-cells.Until HIV appeared on the scene, retroviruses did not kill their host cells. This is the reason they were considered possible tumor viruses. Since retroviruses integrate their genes into the chromosome of the host, they can only replicate as long as the host survives integration and remains able to express integrated viral genes. Therefore a cytocidal retrovirus would be suicidal. Indeed, HIV proved to be non-cytocidal. It is mass-produced for the "AIDS-test" in immortal T-cells in culture at titers of 106 infectious units per ml.37,38 Luc Montagnier and others have confirmed that HIV does not kill T-cells.39-42 Hence the claim that HIV causes AIDS by killing T-cells is paradoxical.

The new papers have indeed resolved this paradox by shifting the paradigm: According to Maddox, T-cells "that harbour virus will be killed off very soon"-but not by HIV-by the immune system. Also consistent with a non-cytocidal virus, Wei et al. report that "the average half-life of infected PBMCs [peripheral blood mononuclear cells] is very long and of the same order of magnitude as the half-life of uninfected PBMCs." But, paradoxically, the same investigators also report that "the life span of virus-producing cells is remarkably short (t1/2 = 2± 0.9 days)," although these cells are in the same system as their long-lived HIV-infected peers.1 Ho et al. state that "there is virus- and immune-mediated killing of CD4 lymphocytes."2 According to the News and Views article by Simon Wain-Hobson "an intrinsic cytopathic effect of the virus is no longer credible."43

It is consistent with this "new view of HIV" that there is no correlation between virus titers and T-cell counts in the patients that Wei et al. and Ho et al. have studied. In some of Ho et al.'s patients, i.e. #303 and #403, a 100-fold variation in virus titers corresponds to no changes in T-cell counts. In Wei et al.'s patients 100-fold variations in virus titers correspond to only 0.25 and 3-fold variations in T-cell counts-hardly a correlation to prove that HIV kills T-cells.

Since HIV is no longer viewed as a T-cell killer, the above paradox is solved. However, if T-cell killing via antiviral immunity were the cause of AIDS, we would have a bigger HIV-AIDS paradox than before. Since only 1 in 500 T-cells are ever infected, and most of these cells contain latent HIV not making viral proteins,25,26,30,44 only less than 1 in 500 T-cells could ever be killed by antiviral immunity.

(2) How HIV causes AIDS.Until HIV appeared on the scene, the pathogenicity of a virus was a direct function of the number of virus-infected cells: the more infectious virus there was, the more cells were infected, and the more pathogenic an infection was.

But in typical AIDS patients HIV is so rare, that even leading AIDS retrovirologists from the US, like Robert Gallo, and the UK, like Robin Weiss, failed for years to isolate HIV from AIDS patients.45,46 Likewise, virus-infected cells are so rare that they could not be found by George Shaw, the senior investigator of the new study by Wei et al., Gallo and their collaborators in most AIDS patients27-until the rare proviral DNA could be amplified with the polymerase chain reaction (PCR).31,44,47

Although the new studies never mention the percentage of infected T-cells, Maddox confirms the status quo: "the scarcity of T-cells from which virus can be recovered in test-tube experiments is consistent with the assertion that the immune system is in overdrive from the onset of infection by HIV." But the new studies claim on average 105 units of "free virus"1or "plasma virion" per ml blood2 in AIDS patients. That should be enough virus to eliminate all remaining T-cells of these patients, 105 per ml, within the two days HIV needs to replicate48-unless, as Maddox suggests, the "new techniques for assaying the low levels of virus involved were also necessary"3 (amplifying viral RNA with the polymerase chain reaction) possibly because no infectious HIV could be detected by conventional infectivity tests.

Indeed, Wei et al. acknowledge "substantial proportions of defective or otherwise non-infectious virus." "To determine whether the viral genomes represented in total viral nucleic acid correspond to infectious virus ..." they had to resort to the same techniques that the "old HIV hands," as Wain-Hobson calls them,43 had used to isolate HIV from rare infected lymphocytes of AIDS patients: "We cocultivated PBMCs ... with normal donor lymphoblasts in order to establish primary virus isolates." Shaw together with some of the investigators of Wei et al. had shown in 1993 how to convert "plasma viral RNA" to infectious virus. They concluded that the "quantitative competitive PCR" is "as much as 60,000 times more sensitive"49 than infectious virus.16, 19 Divide 105 "plasma viral RNA" units by 60,000 and you have 1.6 infectious units per ml, a number that is consistent with numerous previous reports (see above). Ho and a different group of collaborators just published a paper in which they show that over 10,000 "plasma virions," detected by the "branched DNA signal-amplification assay" used in their Nature paper correspond to less than one (!) infectious virus.50 Thus Wei et al. and Ho et al. both reported titers of 105 biochemical virus-units that really correspond to one or even less than one infectious virus. However, infectivity is the only clinically relevant criterion of a virus.

In other words, there is no evidence for infectious virus in Wei and Ho et al.'s patients. Wei and Ho et al. had apparently detected non-infectious virus that had been neutralized by "the immune system [that] reacts hyperactively to HIV infection"-just as Maddox suggests. Infectious virus was only obtained by activating latent HIV from a few infected cells out of millions of mostly uninfected cells from a given AIDS patient. Such virus activation is only achieved by growing cells in culture away from the hyperactive immune system of the host, just as the "old HIV hands" used to do it, when they tried to isolate HIV from AIDS patients.45,46 Thus the paradox of too few viruses to cause immunodeficiency remains unresolved.

In view of the evidence that there are no more than 1.6 infectious HIVs per ml blood in Wei's and Ho's patients, one wonders whether the 105 viral RNAs per ml are real or are an artifact reflecting inherent difficulties in quantifying the input number of "plasma viral RNA" molecules after many rounds of amplification by the PCR. The problem with the quantification of input RNAs-after 30 to 50 rounds of amplification by the PCR51-is like calculating the number of the original settlers in America, from the current number of Americans and their current growth rates. But even if the 105 "plasma viral RNAs" per ml were real, it is hard to guess where they came from in view of "the scarcity of T-cells from which virus can be recovered ..." acknowledged by Maddox.3

However, the apparent lack of infectivity of the "free virus" or "virions"2 resolves the paradox of the coexistence of 105 T-cells with 105 plasma viral RNAs per ml blood in Ho et al.'s and Wei et al.'s AIDS patients.1 Even HIV cannot kill T-cells that it can not infect. The fact that over 99% of T-cells in persons with AIDS are not infected by HIV,14, 26, 27, 31, 32, 44 is definitive evidence that there is no infectious HIV in typical AIDS patients. Clearly, in AIDS patients with 1.6 infectious HIV units per ml something other than HIV must cause AIDS.

In earlier efforts to resolve the paradox, that there is too little HIV in AIDS patients to cause AIDS, both groups have observed huge discrepancies between virus titers and AIDS symptoms. In 1993, George Shaw and colleagues have described otherwise identical AIDS patients of which 5 contained 0 infectious HIV per ml, and 22 contained between 5 and 105.16,19 In 1989, David Ho et al. have also described 40 AIDS patients with virus titers ranging from less than 1 to 105 infectious units per ml.30 In 1993, Ho et al. even reported 12 AIDS patients, including 8 who had AIDS "risk factors," who were totally HIV-free: "Specific antibody assays, viral cultures, and polymerase chain reaction (PCR) techniques" for HIV were all negative. Their T-cell counts ranged from 3 to 308 per µl.52

There is only one consistent hypothesis to reconcile the bewildering ranges of HIV titers in Ho's and Shaw's patients with the role of the virus in AIDS-HIV is a passenger virus, rather than the cause of AIDS. Indeed, non-correlation between the titers of a virus and disease, and between the very presence of a virus and disease-is one of the hallmarks of a passenger virus. Both Ho et al. and Shaw et al. have failed to understand that rare correlations between a virus-at-high-titer and a disease are the hallmark of a passenger virus, and that consistent correlations between a virus-at-high-titer and a disease are the hallmark of causative virus.8, 53, 54 Therefore they have, contrary to their claims, established HIV as a passenger virus of AIDS patients.

(3) Why HIV needs 10 years to cause AIDS.Until HIV appeared on the scene, the latent period from infection to disease was a function of the generation time of a virus. A virus that replicates in 2 days and produces 100 viruses per generation would cause disease in about two weeks-provided there is no antiviral immunity. This is because 100 viruses infect 100 cells producing 100 x 100 or 10,000 viruses 2 days later. Within 14 days of such exponential growth 1014 cells-the equivalent of a human body-would be infected. Therefore the latent periods of pathogenic retroviruses, like Rous sarcoma virus, and non-retroviruses like flu, measles, mumps, herpes, hepatitis, mononucleosis, chicken pox are all 7 to 14 days.23. Since HIV replicates in 2 days, like all other retroviruses,48 and since according to Ho an infected cell produces over 1000 viruses per 2 days,32 HIV should cause AIDS,-if it could cause AIDS-just as fast as other viruses.

Yet, as Maddox points out, the failure of HIV to cause AIDS within weeks after infection presents another paradox for the HIV-AIDS hypothesis, "... the usually slow decline of CD4+ cells is not consistent with what one would expect from a specific cytotoxic viral mechanism." Indeed, both studies confirm the paradox. Since the AIDS patients contain 105 "free viruses/virions" and 105 T-cells per ml plasma, the plasma of these patients should be T-cell free within 2 days, the generation time of HIV. But Ho et al. report that the T-cells of AIDS patients are either steady or even increasing over 1 month, and Wei et al. report that the T-cells of their patients remain either steady or decline slowly over 5 to 8 months.1,2

Even if there are 50-times more T-cells in hidden reservoirs-as Ho et al. report-, they, too, should be infected within two weeks, because according to Wei et al., the "plasma viral RNA" titer can rise two orders of magnitude within two weeks. In fact, the ability of HIV to increase from 103 "plasma viral RNA" units to 105 units per ml described by Wei et al. should only be a fraction of the real "dynamics of the infection of people by HIV,"3 since it occurred despite the presence of two DNA chain terminators, AZT and ddI, used as anti-HIV drugs in addition to a new coded antiviral drug.

Therefore it remains paradoxical that-dated from the time of HIV infection-AIDS occurs at entirely unpredictable times, currently estimated to average 10 years.5 To determine whether the currently unpredictable time from HIV infection to AIDS can be reconciled with a viral mechanism at all, one needs to know whether HIV kills T-cells, how much infectious virus there is, and the percentage of infected cells at a given time. Since the new studies by Wei et al. and Ho et al. provide none of these data, all new calculations "on the dynamics of the infection of people by HIV ... in the process of understanding the disease called AIDS" are worthless.

However, the hypothesis that HIV is a passenger virus provides a consistent explanation for the unpredictable time intervals between HIV infection and AIDS. It is one hallmark of a passenger virus, that the time of infection is unrelated to, and independent of the time when a disease occurs-just as with HIV and AIDS. Another hallmark of a passenger virus is that its titer and even its presence are not correlated with disease-just as was shown above for HIV and AIDS.

The simplest interpretation of the slow decline of T-cells in Ho's and Wei's AIDS patients is a non-viral cause, e.g. long-term intoxication.7 Take for example the slow decline of liver cells in long-term alcoholics or of lung cells in long-term smokers.

Maddox seems concerned that "reporting of the new event has been curiously selective." Perhaps even science reporters begin to wonder how much further the virus-AIDS hypothesis can be stretched to explain its most obvious failures and inconsistencies: Why is there no vaccine? Why does American/European AIDS stay in the classical risk groups, male homosexuals, intravenous drug users and transfusion recipients? Why do AZT-treated HIV-positives get AIDS?55,56 Why do 918 HIV-positive male homosexuals who had "avoided experimental medications on offer" and chose to abstain or significantly reduce their use of recreational drugs ..." remain AIDS-free, long-term survivors?57 Why did the T-cells of 29% of 1020 HIV-positive male homosexuals and former intravenous drug users from the placebo arm of a clinical AZT trial increase up to 22% over two years-despite the presence of HIV?58 Why did the T-cells of 14 out of 31 HIV-positive hemophiliacs treated with highly purified factor VIII increase up to 25% over three years-despite the presence of HIV?59 Why is there not a single study showing that HIV-positive 20 to 50-year-old men or women who are not drug users or recipients of transfusions ever get AIDS?60

Why did neither Ho et al. nor Wei et al. identify the risk groups their patients came from or indicate whether they had Kaposi's sarcoma, dementia, or diarrhea or lymphoma? Can they exclude that recreational drugs used by AIDS risk groups, like nitrite inhalants, amphetamines, and cocaine are immunotoxic or carcinogenic?61 Why is it that among 10 long-term (10 to 15 years) survivors of HIV recently described by Ho et al.50 "none had received antiretroviral therapy ..."? Can Wei et al. and Ho et al. exclude that the DNA chain terminators, AZT and ddI, that their patients received in addition to the new experimental drugs, do not play any role in the "slow decline of CD4+ cells"? Are they aware that the manufacturer of AZT says in the Physician's Desk Reference that "it was often difficult to distinguish adverse events possibly associated with zidovudine [AZT] administration from underlying signs of HIV diseases ..."?62 Are they aware that the DNA chain terminators were developed 30 years ago to kill growing human cells for chemotherapy, not as anti-HIV drugs?

It seems to us that the "new developments" of Wei et al. and Ho et al. are a Mayday of AIDS virologists-rather than a "virological mayhem."43

Acknowledgments

We thank Serge Lang (Yale University), Siggi Sachs (UC Berkeley) and Russel Schoch (UC Berkeley) for critical comments. Supported by the Council for Tobacco Research, USA, and private donations.

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Letter from John Maddox to Peter Duesberg

2 March 1995

Nature
4 Little Essex St.
London, WC2R 3LF

Peter H Duesberg
Department of Molecular and Cell Biology
University of California
Berkelety, CA 94720

Dear Peter,

First, the good news: we shall publish the essence of what you have to say. But there are obvious snags. Let me retail my original conversation with Harvey Bialy. What format? he asked. A letter, I said. That's too little, he said; what about 1,000 words. I said I was not prepared to negotiate the length of a letter not yet written. But what you have sent would take at least 3 pages of Nature.

Second, I resent the way in which you appear to have alerted the world's press to the existence of your piece. Why do that?

Third, and this may not be such good news, I plan to go through your piece with a fine-tooth comb with the intention of ridding it of repetitions and various misrepresentations.

Let me illustrate the last point by reference to your page 3 and the continuation of the main paragraph on page 4. You start with the phrase "HIV was proposed to follow an entirely unprecedented course of action," you document various misconceptions about the functioning of HIV and then you conclude with the phrase "this HIV-hypothesis." Frankly, that smacks of the old Goebbels technique, that of creating a straw man from a farrago of indefensible propositions and then knocking it down. I know of nobody who, in the past decade, has put forward your points (1) to (5) as a unified statement of the conventional position. (Even you have to assemble the position with 20 references.) On the contrary, the "HIV-hypothesis" is much simpler: "HIV causes AIDS, in some manner not understood; most of those infected will develop the disease."

Nor is it a fair representation of Wei et al. and Hoet al. to say that they "claim" to resolve the three specific "paradoxes" you list. In truth, they do nothing of the kind. The only conceivable reference to the 10-year latency period, for example, is in Ho et al., and consists of the simile of the tap and drain. To quote from Wei et al., "The kinetics of virus and CD4+ lymphocyte replication" imply "First, ... continuous rounds of de novo virus infection, replication and rapid cell turnover ... probably represent a primary driving force in HIV pathogenesis ... Second ... a striking capacity of the virus for biologically relevant change. Third ... that virus production per se is directly involved in CD4+ cell destruction." Ho et al. go further, but only to this extent: " ... our findings strongly support the view that AIDS is primarily a consequence of continuous high-level replication of HIV-1, leading to virus and immune-mediated killing of CD4 lymphocytes."

My position as an editor is that straight misrepresentations such as these have no place in a journal like this. You complain at an earlier stage that I have improperly "personalized" this argument. How do you suppose that Wei et al. and Ho et al. would feel if we were to publish your travesty of what they have said?

My suggestion, therefore, is that you throw away the first four pages of your introduction, and devise a less inflammatory introduction in which you state that the two papers have not changed your view, and go on to give the reasons. Please let me know whether that is acceptable. I have some other less radical comments on the remainder of the text, but there's no point in sending them at this stage if you cannot agree to something along the lines I have suggested.

Yours sincerely,

John Maddox
Editor
cc: Harvey Bialy

Letter from Peter Duesberg to Nature

7 March 1995

Sir John Maddox
Nature, Macmillan Publishing
4 Little Essex St., London WC2R 3LF
England

Dear John,

After you have invited us with an editorial "to comment" on "the new view of HIV" (Nature, 19 January 1995), we are surprised to learn that you only want to "publish the essence of what [we] have to say."

We have followed your advice that "it should be no longer than it needs to be." Since neither of the two new Nature studies nor the two accompanying News and Views by you and Wain-Hobson have explained the old view of HIV, we had to explain the old view first for the reader of Nature to understand our comments on "the new view of HIV." We are not interested in a discussion between experts restricted just to titers of HIV. Therefore we cannot accept your suggestion to "throw away the first four pages" of our commentary.

Moreover, if our commentary comes out to be 3 pages in Nature, as you say, that would only be a fourth of the space you have already dedicated to the "new view of HIV"-10 pages for the two papers and 2 pages for the two editorials. A 3-page commentary on 12 pages in Nature, supplemented by an international press release, is hardly a convincing argument that "it is longer than it needs to be."

You write that you "resent the way in which [we] appear to have alerted the world press to the existence of [our] piece." However, we are afraid, if alerting the world's press is a reason for resentment, we should resent you. After all, you have alerted the world's press using the power of your office about the "embarrassment for Duesberg" and that you "eagerly awaited" our "comment." But you did not respond to our commentary from February 7 until March 2. As a result of your activities the world's press has called us, and some callers were given our commentary, weeks after you had received it, with the proviso that it may not be published in its present form by Nature. Indeed, the exchange of opinions is protected by the free-speech amendment in this country.

Are you aware that both Wei et al. and Ho et al. gave their papers to John Coffin and David Baltimore prior to publication in Nature to write editorials for Science (267, 483, 1995) and NEJM (332, 259-260, 1995) respectively?

If you plan to meet your published commitment that "his [Duesberg] and his associates' views on the new developments should be made public" by first cutting, and then editing our commentary with a "fine-tooth comb with the intention of ridding it of ... various misrepresentations," we do not see a basis for an open debate with you.

In response to your letter we resubmit our manuscript with some revisions:

1) page 2, third paragraph: Replace "despite these 'new studies'" by "in light of these new studies."

2) page 2, fourth paragraph: Insert after "immunodeficiency syndrome (AIDS)," "if antibody to HIVis present."

3) page 3, item (2): According to Shaw, Ho and their collaborators, HIV activity is "rapidly and effectively limited" by this antiviral activity.17,18

4) page 4, second paragraph: Replace the sentence "The new studies claim to resolve ..." by "The new studies are claimed by two News and Views articles from Maddox (3) and Wain-Hobson (43) to resolve the paradoxa, (I) How HIV kills T-cells, (II) how HIVcauses AIDS, and (III) why HIVneeds 10 years to cause AIDS."

5) page 6, end; Insert the following paragraph after "... numerous previous reports (see above)": "Ho and a different group of collaborators just published a paper in which they show that over 10,000 "plasma virions," detected by the "branched DNA signal-amplification assay" used in the Nature paper correspond to less than one (!) infectious virus.50 Thus Wei et al. and Ho et al. both reported titers of 105 biochemical virus-units that really correspond to one or even less than one infectious virus. However, infectivity is the only clinically relevant criterion of a virus."

6) page 11: Insert after "are immunotoxic or carcinogenic?" "Why is it that among 10 long-term (10 to 15 years) survivors of HIV recently described by Ho et al.50 'none had received antiretroviral therapy ...'?"

References

17. Daar, E.S., Moudgil, T., Meyer, R.D. &Ho, D.D. N. Engl. J. Med. 324: 961-964 (1991).

18. Clark, S. J., et al., N. Engl. J. Med. 324: 954-960 (1991).

50. Cao, Y., Quin, L. Zhang, L., Safrit, J. & Ho. D.D. N. Engl. J. Med. 332: 201-208 (1995).

Sincerely,

Peter Duesberg, Harvey Bialy (faxed)

On May 18, 1995, Nature published a Duesberg-Bialy letter flanked by two editorial comments:

1) "AIDS pathology unknown"

HIV infection provokes hyperactivity of the immune system, but the causes of that are far from understood.

The clutch of contributions to Scientific Correspondence (page 193) this week deserves a reading, both for its inherent interest and for what it says about the present state of AIDS research. It will be recalled this journal published in January an account of research that showed that the infection of a person by the virus HIV ordinarily evokes not the previously suspected quiescence of the immune system, but a rapid turnover both of the vulnerable lymphocytes and of the virus itself. The then-general opinion that the first reaction of the human body to infection by HIV is a kind of indifference was dramatically and directly challenged. Nothing that has since come to light denies the challenge. But it has also become plain that too little is yet known of the dynamics of the immune system. That is a gap to fill.

The second arresting feature of this correspondence is the letter from Dr. Peter Duesberg and his colleague, Dr. Harvey Bialy, which has been published without change. Sadly, there seems no way in which the authors concerned can be persuaded that "free and fair scientific debate" is ordinarily understood to mean a progressive process, one in which each of two sides learns from what the other says. A restatement of earlier and well-known positions is not that at all. On this occasion, Duesberg and Bialy's citation of Loveday in their cause is especially inappropriate, given Loveday's name among the authors of a letter supporting Wei et al. and Ho et al. But no further solicitation of Duesberg's opinion is called for.

2) "HIV an illusion"

SIR-In an editorial in the 19 January issue of Nature, John Maddox invited "Duesberg and his associates" to comment on the "HIV-1 dynamics" papers published the previous week, indicating that these new results should prove an embarrassment to us. Although we do not think that a scientist should be embarrassed for pointing out inconsistencies and paradoxes in a hypothesis that have only been reportedly resolved 10 years later, we nonetheless prepared a fully referenced, approximately 2,000-word critique of the Ho et al.2 and Wei et al.3 papers that we believed met the criteria of "not being longer than it needs to be, and pertaining to the papers at hand" that Maddox set out in his widely read challenge.

Unfortunately, he did not share our view and agreed to publish only a radically shortened version, and only after he had personally "gone over it with a fine-tooth comb" to remove our perceived misrepresentations of the issues. We found these new conditions so totally at variance with the spirit of free and fair scientific debate that we could not agree to them.

Readers of Nature who are interested in these questions, and feel that they do not need to be protected by Maddox from our ill-conceived logic, can find the complete text of our commentary in the monograph supplement to the most recent issue of Genetica4. Here we would point out only that the central claim of the Ho et al.2 and Wei et al.3 papers-that 105 HIV virions per ml plasma can be detected in AIDS patients with various nucleic-acid amplification assays is misleading. The senior author of the Wei et al. paper has previously claimed that the PCR method they used overestimates by at least 60,000 times the real titer of infectious HIV5: 100,000/60,000 is 1.7 infectious HIVs per ml, hardly the "virological mayhem" alluded to by Wain-Hobson.6 Further, Ho and a different group of collaborators have just shown7 that more than 10,000 "plasma virions," detected by the branched-DNA amplification assay used in their Nature paper, correspond to less than one (!) infectious virus per ml. And infectious units, after all, are the only clinically relevant criteria for a viral pathogen.

Finally, in view of Wain-Hobson's statement6 that "the concordance of their [Wei and Ho's] data is remarkable," note that Loveday et al.8 report the use of a PCR-based assay and find only 200 HIV "virion RNAs" per ml of serum of AIDS patients-1,000 times less than Ho and Wei. So much for the "remarkable concordance."

Peter Duesberg
Department of Molecular and Cellular Biology,
University of California,
Berkeley, California 94720, USA

Harvey Bialy

Bio/Technology, New York, New York 10010, USA

Notes and References

1. Maddox, J. Nature 373, 189 (1995).

2. Ho, D. D. et al. Nature 373, 123-126 (1995).

3. Wei. X. et al. Nature 373, 117-122 (1995).

4. Duesberg, P. & Bialy, H. Genetica Suppl. (in the press).

5. Piatak, M. et al. Science 259. 1749-1754 (1993).

6. Wain-Hobson, S. Nature 373, 102 (1995).

7. Cao, Y. et al. New Engl. J. Med. 332, 201-208 (1995).

8. Loveday, C. et al. Lancet 345, 820-824 (1995).

3) Editorial Statement

This letter was followed by the editorial statement: "Peter Duesberg was offered space in Scientific Correspondence for 500 words of his own choice, but declined.-Editor, Scientific Correspondence."

Letter from Peter Duesberg to John Maddox

Sir John Maddox
Editor, Nature
Porters South, Crinnan St.
London, England

10 July 1995

Dear John,

Following publication of the Duesberg-Bialy letter on May 18, Nature added: "Peter Duesberg was offered space in Scientific Correspondence for 500 words of his own choice but declined."

Since our letter used up that "space," Nature's comment is erroneous and should be retracted.

Could you please confirm or un-confirm our conclusion. I have faxed to you twice before requesting an answer to this question (June 20 and June 22, 1995) but have not received a reply.

Sincerely,

Peter Duesberg

cc: Harvey Bialy

Letter from Nature to Peter Duesberg

Nature
Porters South, 4-6 Crinan Street
London, England

19 July 1995

Dr. P. Duesberg

Department of Molecular and Cell Biology
University of California
Berkeley, CA 94720

Dear Dr. Duesberg,

Thank you for your various faxes. We offered to publish a 500-word version of your response to Ho/Shaw in our issue in which we published other comments on those papers. You declined, and instead sent us a complaint that we would not publish your long manuscript. We published that complaint. As far as we are concerned, the matter rests.

Yours sincerely,

Dr. Maxine Clarke

Executive Editor, Nature