RETHINKING AIDS HOMEPAGE
July 29, 1988.
HIV Is Not the Cause of AIDS
Human immunodeficiency virus (HIV) is not the cause of AIDS because
it fails to meet the postulates of Koch and Henle, as well as six cardinal
rules of virology.
1) HIV is in violation of Koch's first postulate because it is not possible
to detect free virus (1, 2), provirus (3-5), or viral RNA (4, 6, 7) in
all cases of AIDS. Indeed, the Centers for Disease Control (CDC) has established
guidelines to diagnose AIDS when all laboratory evidence for HIV is negative
2) In violation of Koch's second postulate, HIV cannot be isolated from
20 to 50% of AIDS cases (1, 9-11). Moreover, "isolation" is very
indirect. It depends on activating dormant provirus in millions of susceptible
cells propagated in vitro away from the suppressive immune system of the
3) In violation of Koch's third postulate, pure HIV does not reproduce
AIDS when inoculated into chimpanzees or accidentally into healthy humans
(9, 12, 13).
4) In contrast to all pathogenic viruses that cause degenerative diseases,
HIV is not biochemically active in the disease syndrome it is named for
(14). It actively infects only 1 in 104 to > 105 T cells (4, 6, 7, 15).
Under these conditions, HIV cannot account for the loss of T cells, the
hallmark of AIDS, even if all infected cells died. This is because during
the 2 days it takes HIV to replicate, the body regenerates about 5% of
its T cells (16), more than enough to compensate for losses due to HIV.
5) It is paradoxical that HIV is said to cause AIDS only after the onset
of antiviral immunity, detected by a positive "AIDS test," because
all other viruses are most pathogenic before immunity. The immunity against
HIV is so effective that free virus is undetectable (see point 1), which
is why HIV is so hard to transmit (9, 12, 13). The virus would be a plausible
cause of AIDS if it were reactivated after an asymptomatic latency, like
herpes viruses. However, HIV remains inactive during AIDS. Thus the "AIDS
test" identifies effective natural vaccination, the ultimate protection
against viral disease.
6) The long and highly variable intervals between the onset of antiviral
immunity and AIDS, averaging 8 years, are bizarre for a virus that replicates
within 1 to 2 days in tissue culture and induces antiviral immunity within
1 to 2 months after an acute infection (9, 17). Since all genes of HIV
are active during replication, AIDS should occur early when HIV is active,
not later when it is dormant. Indeed, HIV can cause a mononucleosis-like
disease during the acute infection, perhaps its only pathogenic potential
7) Retroviruses are typically not cytocidal. On the contrary, they often
promote cell growth. Therefore, they were long considered the most plausible
viral carcinogens (9). Yet HIV, a retrovirus, is said to behave like a
cytocidal virus, causing degenerative disease killing billions of T cells
(15, 18). This is said even though T cells grown in culture, which produce
much more virus than has ever been observed in AIDS patients, continue
to divide (9, 10, 18).
8) It is paradoxical for a virus to have a country-specific host range
and a risk group-specific pathology. In the United States, 92% of AIDS
patients are male (19), but in Africa AIDS is equally distributed between
the sexes, although the virus is thought to have existed in Africa not
much longer than in the United States (20). In the United States, the virus
is said to cause Kaposi's sarcoma only in homosexuals, mostly Pneumocystis
pneumonia in hemophiliacs, and frequently cytomegalovirus disease in children
(21). In Africa the same virus is thought to cause slim disease, fever,
and diarrhea almost exclusively (22, 23).
9) It is now claimed that at least two viruses, HIV-1 and HIV-2, are
capable of causing AIDS, which allegedly first appeared on this planet
only a few years ago (20). HIV-1 and HIV-2 differ about 60% in their nucleic
acid sequences (24). Since viruses are products of gradual evolution, the
proposition that within a few years two viruses capable of causing AIDS
could have evolved is highly improbable (25).
See Blattner and colleagues respond to Duesberg below
References and Notes:
1.J. Albert et al., J. Med. Virol. 23, 67 (1987).
2.L.A. Falk, D. Paul, A. Landay, H. Kessler, N. Engl.
J. Med. 316, 1547 (1987).
3.G.M. Shaw et al., Science 226, 1165 (1984).
4.D. Richman, J. McCutchan, S. Spector, J. Infect Dis.
156, 823 (1987).
5.C.-Y. Ou et al., Science 239, 295 (1988).
6.M.E. Harper, L.M. Marselle, R.C. Gallo, F. Wong-Staal,
Proc. Natl. Acad. Sci. U.S.A. 83, 772 (1986).
7.A. Ranki et al., Lancet ii, 589 (1987).
8.Centers for Disease Control, J. Am. Med. Assoc. 258,
9.P.H. Duesberg, Cancer Res. 47, 1199 (1987).
10.H. von Briesen et al., J. Med. Virol. 23, 51 (1987).
11.D. Gallo, J. Kimpton, P. Dailey, J. Clin. Microbiol.
25, 1291 (1987).
12.J.W. Curran et al., Science 239, 610 (1988).
13.G.H. Friedland and R.S. Klein, N. Engl. J. Med. 317,
14.J. Coffin et al., Science 232, 697 (1986).
15.A. Fauci, ibid. 239, 617 (1988).
16.J. Sprent, in B and T Cells in Immune Recognition,
F. Loor and G.E. Roelants, Eds. (Wiley, New York, 1977), pp. 59-82.
17.H.A. Kessler, J. Am. Med. Assoc. 258, 1196 (1987).
18.R.C. Gallo, Sci. Am. 256 (No. 1), 47 (1987).
19.Centers for Disease Control, AIDS Weekly Surveill.
Rep., 18 April 1988.
20.R. Baum, "AIDS: The molecular biology," Chem.
Eng. News (23 November 1987), pp. 14-26.
21.R.M. Selik, E.T. Starcher, J.W. Curran, AIDS 1, 175
22.R. Colebunders et al., Lancet i, 492 (1987).
23.K.J. Pallangyo et al., ibid. ii, 972 (1987).
24.F. Clavel et al., Nature 324, 691 (1986).
25.J. Sonnabend, in New York Native (9 May 1988), p. 19.
Blattner and Colleagues Respond to Duesberg
Biology is an experimental science, and new biological phenomena are
continually being discovered. For example, recently some RNA molecules
were shown to act as enzymes, ribozymes, even though biochemistry text
books state that all enzymes are proteins. Thus, one cannot conclude that
HIV-1 does or does not cause AIDS from Duesberg's "cardinal rules"
of virology. In fact, the Henle-Koch postulates of 1840 and 1890 were formulated
before the discovery of viruses. They are a useful historical reference
point, but were not regarded as rigid criteria by Koch himself and should
not be so regarded today (1).
Duesberg's description of the properties of viruses is in error and
provides no distinction between knowing the cause of a disease, that is,
its etiology, and understanding the pathogenesis of this disease. Duesberg
is noted for his discoveries about the viral oncogene src. There is no
question that the expression of this gene in chicken fibroblasts results
in sarcomas. However, no one can yet explain how the expression by the
src oncogene of an altered tyrosine protein kinase results in a cell becoming
neoplastic. Similarly, there are many unanswered questions about the pathogenesis
of AIDS, but they are not relevant to the conclusion that HIV causes AIDS.
Duesberg presents six (or nine) cardinal rules for viruses. Most are
not relevant to the question of etiology and are misleading or wrong about
viruses in general and HIV in particular.
1-2) It was formerly true that evidence for the presence of HIV-1 could
not be found in all AIDS patients. But the overwhelming seroepidemiologic
evidence pointing toward HIV as the cause of AIDS spurred research to improve
the sensitivity of the detection methods. Better methods of virus isolation
now show that HIV infection is present in essentially all AIDS patients
The CDC definition of AIDS has been revised several times as new knowledge
has become available and will undoubtedly be revised again. The 1981 CDC
definition of AIDS did not mention HIV, since no strain of HIV was known
until 1983. Many cases of AIDS are diagnosed on clinical grounds alone
because of the lack of availability or expense of HIV-1 antibody testing
or because HIV testing is discouraged in some communities. Thus, rates
of confirmation of AIDS cases by HIV testing in the United States vary
geographically as reflected in CDC surveillance statistics.
3) It is true that HIV does not cause AIDS in chimpanzees. Most viruses
are species-specific in host range and in capacity to produce disease.
For example, herpes B virus, yellow fever virus, and dengue virus cause
serious diseases in humans, but produce no disease symptoms during infection
in many species of monkeys (3). Moreover, a virus closely related to HIV,
simian immunodeficiency disease virus or SIV, causes an AIDS-like disease
in rhesus macaques, but seldom, if ever, causes immunodeficiency in African
Green monkeys (4, 5).
HIV-1 does indeed cause AIDS when inoculated into humans with no underlying
medical condition. Accidental needlestick injuries with HIV-contaminated
needles have resulted in HIV seroconversion and then clinical AIDS (6).
4) It is true that HIV infects only a small fraction of T cells. However,
about 15% of the macrophage and monocyte cells from AIDS patients are positive
for a viral protein, p24 (7), and the high concentration of this protein
in the blood of AIDS patients indicates virus activity (8). The exact mechanism
of CD4 cell depletion in AIDS patients is not known, but several indirect
mechanisms are known by which HIV can cause CD4 cell depletion in laboratory
studies and could operate in vivo.
5-6) Many viruses are highly pathogenic after evidence of immunity appears.
For example, reactivated herpes zoster virus causes shingles, and reactivated
herpes simplex virus causes local lesions as well as lethal necrotizing
encephalitis; moreover, hepatitis B virus causes chronic active hepatitis,
equine infectious anemia virus causes anemia, and visna virus causes central
nervous system degeneration after the appearance of specific neutralizing
antibodies (3, 9). (The last two viruses are lentiretroviruses as is HIV.)
These diseases also can have long and variable latent periods.
7) It is true that some retroviruses, in particular, the highly oncogenic
retroviruses of the kind that Duesberg has worked with, are not cytocidal
and promote cell growth. Most retroviruses have no effect on cell growth
(9, 10). However, Rous-associated virus-2, spleen necrosis virus, visna
virus, and HIV kill infected cells in culture and can establish a chronic
stage of infection in which surviving infected cells continue to divide
8) It was apparently "paradoxical for a virus to have a country-specific
host range and a risk group-specific pathology." The properties of
HIV resolved this paradox because the distribution of AIDS was found to
mirror the distribution of HIV. The nature of the spread of the virus and
the type of the AIDS-related clinical syndrome depend on social and environmental
factors. Sexually active gay men and parenteral drug abusers were the first
conduit for spread of HIV in the United States, whereas in some developing
countries of Africa, young heterosexually active men and women were the
major focus of spread. It is common for life-style to be a major determinant
for the spread of an infectious agent. For example, until a vaccine became
available, hepatitis B virus was clustered among the same U.S. populations
that are now infected by HIV.
The underlying pathology in AIDS is immune deficiency. The nature of
the opportunistic agents that invade the susceptible host is a function
of which agents are most prominent in a particular population. For example,
in the United States Pneumocystis is most prominent in affluent gay men,
while human mycobacterial infections and toxoplasmosis are more frequent
in socially disadvantaged Caribbean immigrants. Other agents, such as Cryptococcus,
are more prominent in developing countries.
9) It is true that there are two viruses that cause human AIDS, HIV-1
and HIV-2. The origin of these HIVs is an interesting scientific question
that is not relevant to whether or not HIV causes AIDS. Since a primate
lentiretrovirus also causes an AIDS-like disease in rhesus monkeys, just
as a cat lentiretrovirus, feline immunodeficiency virus, causes an AIDS-like
disease in cats (12), one can suggest either that there is strong selection
among retroviruses for this kind of pathology (13) or that the virus ancestor
to HIV already had this property. In favor of the first hypothesis is the
existence of feline, murine, and primate AIDS caused by retroviruses in
a different subfamily from the lentiretroviruses (14).
In summary, although many questions remain about HIV and AIDS, a huge
and continuously growing body of scientific evidence shows that HIV causes
References and Notes:
1. A.S. Evans, Yale J. Biol. Med. 49, 175 (1976).
2. References 1 and 2 from Duesberg report isolation of
HIV-1 from 100% of AIDS patients; I.S.Y. Chen (UCLA) reports isolation
of HIV-1 from 100% of AIDS patients (personal communication); R.C. Gallo,
M. Popovic, S. Z. Salahuddin, S. Gardner, and co-workers now isolate HIV-1
from more than 90% of AIDS patients. Duesberg's references 5 and 7 do not
report on AIDS patients at all.
3. B.N. Fields et al., Eds. Virology (Raven, New York,
1985); F. Fenner, B.R. McAuslan, C.A. Mims, J. Sambrook, D.O. White, The
Biology of Animal Viruses (Academic Press, New York, ed. 2, 1974).
4. N.L. Letvin et al., Science 230, 71 (1985).
5. Duesberg's reference 13 deals only with HIV-1 transmission,
not disease occurrence.
6. AIDS Program, Hospital Infections Branch, CDC, Morbid.
Mortal. Weekly Rep. 37, 229 (1988). This pattern of AIDS development following
HIV-1 seroconversion is the same as that seen for pediatric and adult blood
transfusion cases and mother-to-child transmission, and in a multitude
of prospective studies of gay men, hemophiliacs, and other populations
in developed and developing countries.
7. S. Crowe, J. Mills, I. Kirihara, P. Lakas, M. McGrath,
Abstracts of the Fourth International Conference on AIDS, Stockholm (1988).
8. G.G. Jackson et al., Ann. Int. Med. 108, 175 (1988).
Macrophages and monocytes and not T cells appear to be the major reservoir
of HIV infection in humans.
9. N. Teich, I. Wyke, T. Mak, A. Bernstein, W. Hardy, in
RNA Tumor Viruses, Molecular Biology of Tumor Viruses, R. Weiss, N. Teich,
H. Varmus, J. Coffin, Eds. (Cold Spring Harbor Laboratory, Cold Spring
Harbor, NY, ed. 2, 1982), pp. 785-998.
10. H.M. Temin, Rev. Infect. Dis. 10, 399 (1988).
11. --. and V.K. Kassner, J. Virol. 13, 291 (1974); J.
Gen. Virol. 27, 267 (1975).
12. N.C. Pedersen et al., Science 235, 790 (1987).
13. H.M. Temin, in Concepts in Viral Pathogenesis, A.L.
Notkins, M.B.A. Oldstone, Eds. (Springer-Verlag, New York, 1988), vol.
14. D.M. Mosier, Immunol. Invest. 15, 233 (1986).
RETHINKING AIDS HOMEPAGE