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By Peter Duesberg
Department of Molecular Biology, Stanley Hall, University of California, Berkeley, CA 94720
Contributed by Peter H. Duesberg, June 14, 1988; revision received October 21, 1988

Original Publication
Proc. Natl. Acad. Sci. USA
Vol.86, pp. 755-764, February 1989
Review

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It has been proposed that pathogenic HIV mutants arise during the long intervals between infection and AIDS and that these mutants might escape antiviral immunity by losing specific epitopes (28, 31, 82, 90, 112, 113, 123, 124) or even by changing their host range from T cells to microphages (44). However, there is no report of a mutant HIV present at high titer in AIDS. Further, it is very unlikely that a mutant could escape an existing immunity, because it would share most variable and, of necessity, all constant determinants with the parent virus. Even though all retroviruses, including HIV (125-128), mutate at a frequency of 1 in 10 [4th power] nucleotides per replicative cycle, they have never been observed to escape an existing antiviral immunity. It has also been proposed that HIV escapes immunity by spreading via cell-to-cell transmission (28, 32, 115, 117, 129). However, consistent with the syncytium-blocking function of natural antibodies (23, 115, 119), there is no spread of HIV in vivo.

Intervals of 2 to 15 Years Between Infection and AIDS Are Incompatible with HIV Replication.

If cytocidal viruses or retroviruses cause disease, they do so within 1 to 2 months of infection (23, 86). By that time, the host's immune system either eliminates the virus or restricts it to latency, or the virus overcomes the immune system and kills the host. Indeed, clinicians have reported that, in rare cases, HIV causes a disease like mononucleosis prior to immunity, presumably due to an acute infection (23, 69, 130, 186). Since this disease correlates with viral activity (69) and disappears within weeks as the body develops antiviral immunity, it may reflect the true pathogenic potential of HIV.

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Thus, the progressive diseases induced by active retroviruses depend on relative tolerance to the virus due to rare native or acquired immunodeficiency or congenital infection prior to immune competence. Since tolerance to HIV that would result in active chronic infection has never been observed and is certainly not to be expected for 50-100% of infections (the percentage of infections said to develop into AIDS (ref. 7 and above)), the rare retrovirus infections of animals that cause slow, progressive diseases are not models for how HIV might cause AIDS. Indeed, not one acute retrovirus infection has ever been described in humans (23).

The Paradox of How HIV, a Noncytocidal Retrovirus, Is To Cause the Degenerative Disease AIDS.

Unlike cytocidal viruses, which replicate by killing cells, retroviruses need viable cells for replication (139). During retroviral infection, proviral DNA becomes the cellular gene as it is integrated into the DNA of the cell. Such a mechanism is superfluous for a cytocidal virus. Virus reproduction from then on is essentially gene expression in viable cells, often stimu- lating hyperplastic growth (17, 23). Alternatively, retroviruses survive as latent proviruses, like latent cellular genes. The very distinction of not killing the host cell is the reason that scientists have for so long considered retroviruses to be the most plausible viral carcinogens (17, 23, 140).

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The cytocidal effects that are occasionally observed in HIV-infected cultures (but as yet, never in humans) soon after infection do not break this rule (23). These early effects result from fusions of HIV-infected and uninfected cells that depend on virus isolates and cell culture conditions (23, 82, 146, 147), and are completely inhibited by antiviral antibody (23, 115, 119). They are not HIV-specific, because many animal and human retroviruses show conditional, but never absolute, cytocidal effects in cell culture (23). Thus, the fusion effect in culture might be relevant for the mononucleosis observed in some patients soon after infection, when free virus (but no fusion-inhibitory antibody) is present. However, the effect can- not be irrelevant to AIDS because there is plenty of fusion-inhibitory antibody and because the virus isolates from some patients fuse, and those from others don't (23, 82, 146, 147). Thus, HIV is not sufficient to kill even the few T cells it infects in AIDS.

HIV Is a Conventional Retrovirus, Without an AIDS Gene.

The virus-AIDS hypothesis proposes that HIV is an unorthodox retrovirus (6, 12, 14, 31, 32) containing specific suppressor and activator genes that control the 2- to 15-year intervals between infection and AIDS (12, 17, 188). However, the two known HIVs (see below) are profoundly conventional retroviruses. They have the same genetic complexity of about 9150 nucleotides, the same genetic structure, including the three major essential retrovirus genes linked in the order gag-pol-env, the same mechanism of replication, and the same mutation frequency (3, 7, 17, 90, 125, 126, 148) as all other retroviruses (17, 127, 128, 149, 150). Humans carry between 50 and 100 such retroviruses in their germ line, mostly as latent proviruses (151). The presumably specific genes of the HIVs (12, 188) are alternative reading frames of essential genes shared by all retroviruses (3, 7, 12, 23, 90, 148). Their apparent novelty is more likely to reflect new techniques of gene analysis than to represent HIV-specific retroviral functions. Indeed, analogous genes have recently been found in other retroviruses, including one bovine and at least three other human retroviruses that do not cause AIDS (23, 152, 188). Because HIV and all other retroviruses are isogenic, the newly discovered genes cannot be AIDS-specific. Moreover, it is unlikely that these genes even control virus replication. In vivo, HIV lies chronically dormant, although the presumed suppressor genes are not expressed. In vitro, HIV is propagated at titers of about 10 [6th power] per ml in the same human cells in which it is dormant in vivo, although the presumed suppressor genes are highly expressed (23, 188). Therefore, I propose that antiviral immunity rather than viral genes suppress HIV in vivo, as is the case with essentially all retroviruses in wild animals (23). Further, I propose that the multiplicity of AIDS diseases are caused by a multiplicity of risk factors (see below), rather than by one or a few viral activator genes, since viral gene expression in AIDS is just as low as in asymptomatic carriers. Also, the extremely low genetic complexity of HIV can hardly be sufficient to control the inevitably long times between infection and AIDS, and the great diversity of AIDS diseases. Thus, there is neither biochemical nor genetic evidence that HIV genes initiate or maintain AIDS.

The Paradoxes of an AIDS Virus with Country- and Risk-Specific Pathologies and Host Ranges.

It is yet another paradox of the virus-AIDS hypothesis that HIV is said to cause very different diseases in different risk groups and countries. For example, in the U.S. over 90% of AIDS patients have Pneumocystis pneumonia or Kaposi sarcoma. However, Kaposi sarcoma is found almost exclusively in homosexuals (8, 191). By contrast, in Africa over 90% of the AIDS cases are manifested by slim disease, fever, and diarrhea (9, 10, 64). Moreover, it is paradoxical that the prevalence of Kaposi sarcoma among U.S. AIDS cases has shifted down from 35% in 1983 (156) to 6% in 1988 (4) (see below and refs. 190 and 191), and Pneumo-cystis pneumonia has shifted up from 42% to 64% (8), while the alleged cause, HIV, has remained the same.

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A solution of the paradox is that HIV is not new but is endemic in Africa and, like most retroviruses (23), is transmitted perinatally rather than sexually. Accordingly, 10% of healthy Zairians are antibody-positive (46, 98, 184), and not more than 30% of the Kaposi sarcoma patients in Africa are infected with HIV (157, 158). Indeed, perinatal transmission between mother and child occurs with an efficiency of 30-50% (7, 22, 39), while sexual transmission is extremely inefficient (65, 79, 80, 154, 155). Since the virus is not endemic in the U.S., it is transmitted more often by parenteral exposures associated with risk behavior (see below) than perinatally.

Evolutionary Arguments Against AIDS Viruses.

It is now claimed that there are at least two new retroviruses capable of causing AIDS, HIV-1 and HIV-2 (3, 7, 12-14), which differ about 60% in their nucleic acid sequences (148). Both allegedly evolved only 20 to <100 years ago (12). Since viruses, like cells, are the products of gradual evolution, the proposition that, within a very short evolutionary time, two different viruses capable of causing AIDS would have evolved or crossed over from another species is highly improbable (56, 64, 159). It is also improbable that viruses evolved that kill their only natural host with efficiencies of 50-100% as is claimed for the HIVs (7, 33-38).

Conclusions and Perspectives

It is concluded that HIV is not sufficient to cause AIDS because HIV meets neither Koch's postulates nor established epidemiological, biochemical, genetic, and evolutionary criteria of a viral pathogen. Further, it is concluded that HIV may not even be necessary for AIDS because there is neither biochemical nor genetic evidence that it initiates or maintains AIDS. HIV infiltration and activity are just as low in symptomatic carriers as in asymptomatic carriers, and HIV lacks an AIDS gene. The association between AIDS and antibody to HIV -- now part of the definition of AIDS -- does not prove causation because otherwise indistinguishable diseases are now set apart only on the basis of this antibody. According to this view, HIV is an ordinary harmless retrovirus that, in rare acute infections, may cause a mononucleosis-like disease before immunity.

Antibody to HIV Is a Surrogate Marker for Risk of AIDS.

Although HIV does not appear to cause AIDS, it may serve in the U.S. and Europe as a surrogate marker for the risk of AIDS for the following reasons. (i) In these countries, HIV is not widespread but is one of the most specific occupational infections of persons at risk for AIDS (3, 7, 38, 47, 61, 94, 160). (ii) Since HIV is extremely difficult to transmit, like all latent viruses, it would specifically identify those who habitually receive transfusions or intravenous drugs or are promiscuous. Indeed, the probability of being antibody-positive correlates directly with the frequency of drug use (38, 47, 160), transfusions (94, 161), and male homosexual activity (38, 160). (iii) Since HIV is not cytocidal, it persists as a minimally active virus in a small number of cells, which will chronically boost antiviral immunity to produce a positive AIDS test. Latent EBV, cytomegalovirus, or other herpes-virus infections will likewise maintain a chronic immunity (86, 120), although less specific for AIDS risk. By contrast, antibodies against viruses and microbes, which cannot persist at subclinical levels, tend to disappear after primary infection.

Epidemiology is Not Sufficient to Prove Etiology.

It has been argued that Koch's postulates can be abandoned as proof for etiology in favor of epidemiological correlations (67, 68, 162), most recently in the case of HIV (14, 32). How- ever, adherence to this epidemiological concept (68, 162) as a substitute for biochemical and genetic proof of etiology has resulted in some of the most spectacular misdiagnoses in virology. (a) Based on epidemiological correlations, EBV was thought to be the cause of Burkitt pneumonia -- until Burkitt lymphomas free of the virus were discovered (163). (It is ironic that HIV is currently a proposed cause of Burkitt lymphoma (5).) (b) Also on the basis of seroepidemiological evidence, retroviruses were thought to cause human and bovine leukemias after bizarre latent periods of up to 40 years in humans (164), until the discovery of these viruses in billions of normal cells of millions of asymptomatic carriers cast doubt on this hypothesis (23). It is scarcely surprising that the particular T cell from which a rare clonal leukemia originated was also infected. It is consistent with this view that these tumors are clonal and not contagious, like virus-negative leukemias, and that the presumably causative viruses are biochemically inactive in the human and bovine leukemias (23). Instead of viruses, the only specific markers of such tumors are clonal chromosomal abnormalities (23). (c) Likewise, slow viruses have gained acceptance as causes for such diseases as kuru, Creutzfeld-Jacob disease, and Alzheimer disease on the basis of epidemiological evidence (165), although these viruses have never been detected.

Proof of Etiology Depends on Evidence for Activity.

Regrettably, the hasty acceptance of the virus as the cause of AIDS (16), signaled by naming it HIV (18), has created an orthodoxy whose adherents prefer to discuss "how" rather than "whether" HIV causes AIDS. They argue that it is not necessary to understand HIV pathology, or how a latent virus kills, in order to claim etiology (7, 14, 32, 51). Therefore, many different mechanisms, including ones in which HIV is said to depend on cofactors to cause AIDS, have been discussed (6, 12, 31, 32, 35, 61, 91) to explain how the virus supposedly kills at least 10 [4th power] times more T cells than it actively infects (26-28, 71-74). Yet all speculations that HIV causes AIDS through cofactors cast doubt on HIV as a cause of AIDS, until such factors are proven to depend on HIV.

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In response to this, it has been argued that a biochemically inactive HIV may cause AIDS indirectly by a mechanism(s) involving new biological phenomena (12, 14, 31, 32). This is argued even though HIV is like numerous other retroviruses studied under the Virus-Cancer Program during the past 20 years (17, 140), which are only pathogenic when they are biochemically active (23). Nevertheless, some retroviruses (23) and DNA viruses (e.g., hepatitis virus in hepatomas (169)) are thought to cause tumors indirectly by converting, by means of site-specific integration, a specific gene of a rare infected cell to a cancer gene. Such a cell would then grow autonomously to form a monoclonal tumor, in which the virus may be inactive and often defective (17, 23, 140, 169). However, such highly specific, and hence rare, virus-cell interactions cannot explain the loss of billions of cells during a degenerative disease like AIDS. It is also hard to accept that HIV could cause AIDS through a T-cell autoimmunity (12, 31, 32, 170), because it reaches far too few cells to function as a direct immunogen and because it is unlikely to function as an indirect immunogen since it is not homologous with human cells (73, 75, 77). Further, it is extremely unlikely that any virus could induce autoimmunity, which is a rare consequence of viral infection, as efficiently as HIV is thought to cause AIDS, namely in 50-100% of all infections.

Not All AIDS Diseases Can Be Explained by Immunodeficiency.

Clearly, immunodeficiency is a plausible explanation for the microbial and viral AIDS diseases (5) and Pneumocystis pneumonia. However, the effective immunity against HIV, which defines AIDS, together with those against cytomegalovirus, herpes simplex virus, hepatitis virus, and other viruses (3, 23, 61, 94), is hard to reconcile with acquired immunodeficiency. One would have to argue that T-cell depletion in AIDS is highly selective in order to allow Pneumocystis but not HIV or other viruses to become active. If HIV were able to induce T-cell immunodeficiency against itself, its titer during AIDS should be as high as it is in cultures of infected human monocytes -- namely, up to 10 [6th power] infectious units per milliliter (see above), just as high as the titers of all other retroviruses when they are pathogenic in animals (23).

Moreover, immunodeficiency does not explain AIDS neoplasias such as lymphomas or Kaposi sarcoma, which may be a hyperplasia (175, 178). The hypothesis that cancers reflect a defective immune system, the immune-surveillance hypothesis (176), has been disproven through athymic (nude) mice, which develop no more cancers than other laboratory mice (177). In fact, no immunodeficiency was observed in HIV-infected African patients who had Kaposi sarcomas (157, 158). In addition, Kaposi sarcoma tissue does not contain any HIV (23, 178, 179). Immunodeficiency also cannot explain dementia; nor can dementia be explained by HIV infection of neurons, because retroviruses are dependent on mitosis for infection (17, 23, 139, 140) and neurons do not divide (169). HIV would indeed by a mysterious virus (31) to kill T cells and neurons that are not infected and, at the same time, to induce hyperplastic or neoplastic growth of other cells that are also not infected.

HIV Is Not a Rational Basis for AIDS Therapy.

Since there is no proven mechanism of HIV pathogenesis, HIV is not a rational basis for the control of AIDS. Thus the treatment of symptomatic and even asymptomatic HIV carriers with azidothymidine (AZT) (7, 39) cannot be justified in terms of its original design, which is to inhibit HIV DNA synthesis by chain termination (171). Even if HIV were to cause AIDS, it would hardly be a legitimate target for AZT therapy, because in 70-100% of antibody-positive persons proviral DNA is not detectable (73, 75, 187) without amplification (77), and its biosynthesis has never been observed.

Nevertheless, AZT has been claimed to have beneficial effects for AIDS patients on the basis of a 16- to 24-week double-blind trial (194). However, AZT, originally developed for chemotherapy by terminating cellular DNA synthesis, efficiently kills dividing blood cells and other cells (39, 84, 172-174, 189, 193, 195) and is thus directly immunosuppressive. Moreover, the immediate toxicity of AZT (174, 189, 193, 195) suggests that this trial could hardly have been double-blind and hence unbiased.

What Are the Causes of AIDS?

I propose that AIDS is not a contagious syndrome caused by one conventional virus or microbe, because no such virus or microbe would average 8 years to cause a primary disease, or would selectively affect only those who habitually practice risk behavior, or would be able to cause the diverse collection of over 20 degenerative and neoplastic AIDS diseases. Neither could a conventional virus or microbe survive if it were as inefficiently transmitted as AIDS, and killed its host in the process. Conventional viruses either are highly pathogenic and easy to transmit or are nonpathogenic and latent and hence very difficult to transmit (153). Conventional viruses or microbes also exist that cause secondary -- or even primary -- diseases long after infection, but only when they are activated from dormancy by rare acquired deficiencies of the immune system (86). Such opportunistic infections are the consequence rather than the cause of immunodeficiency.

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188. Haseltine, W.A., & Wong-Staal, F. (1988) http://Sci.Am . 259 (4), 52-62.

189. Kolata, G. (1987) Science 235, 1462-1463.

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