TO "DUESBERG AND THE NEW VIEW OF HIV"
By Peter H. Duesberg and Harvey Bialy
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. and Ho et. al. that he feels
lend strong support to the hypothesis that HIV causes AIDS .
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 ususally slow decline
of CD4+ cells [T-cells] is not consistent with... a specific cytotoxic
viral mechanism." 
Maddox, "the new divelopments 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
In 1984 it
was proposed that the retrovirus HIV can cause such diametrically
different diseases as Koposi'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) , 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 10-10^4
infectious units per ml blood , 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 damage 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 undetectably low prior
to and even during AIDS [25-29]. Only in rare cases HIV titers are
as high as in asymptomatic, primary infection [16,30]. But in all
other viral diseases the virus titer is maximally high when viruses
cause disease [20,21].
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].
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 Maddox  and Wain-Hobson
 to resolve the paradox, (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) 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 remaines 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 10^6 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"-not by HIV-but 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 .
Ho et al. state that "there is virus-and immune-mediated killing
of CD4 lymphocytes" . According to the News and Views article
by Simon Wain-Hobson, "an intrinsic cytopathic effect of the
virus is no longer credible" .
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) Until HIV
appeared on the scene, the patogenicity 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 in 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 patients -- until
the rare proviral DNA could be amplified with the polymerase chain
reaction (PCR) [31,44,47].
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
10^5 of "free virus"  of "plasma virion"
per ml blood  in AIDS patients. That should be enough virus to
eliminate all remaining T-cells of these patients, 10^5 per ml,
within the two days HIV needs to replicate -- unless, as Maddox
suggest, the "new techniques for assaying the low levels of
virus involved were also necessary"  (amplifying viral RNA
with the polymerase chain reaction) possibly because no infectious
HIV could be detected by conventional infectivity tests.
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 ,
had used to isolate HIV fom 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"  than infectious virus
[16,19]. Divide 10^5 "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 .
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
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 10^5
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 the input RNAs-after 30 to
50 rounds of amplification by the PCR -- is like calculating
the number of original settlers in America, from the current number
of Americans and their current growth rates. But even if the 10^5
"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 the virus can be recovered..." acknowledged by Maddox
apparent lack of infectivity of the "free virus" or "virions"
 resolves the paradox of the coexistence of 10^5 T-cells with
10^5 plasma viral RNAs per ml blood in Ho et al.'s and Wei et. al.'s
AIDS patients . Even HIV cannot kill T-cells that it cannot 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
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, Shaw and colleagues
have described otherwise identical AIDS patients of which 5 contained
0 infectious HIV per ml, and 22 contained between 5 and 10^5 [16,19].
In 1989, David Ho et.al. have also described 40 AIDS patients with
virus titers ranging from less than 1 to 10^5 infectious units per
ml . 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 ml .
There is only
one consistent hypothesis to reconcile the bewildering ranges of
HIV titers in Ho's and Shaw's patients, that the role of the virus
in AIDS-HIV is a passenger virus, rather than the cause of AIDS.
Indeed, non-correlation between the tiers 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 a causative virus [8,53,54]. They have, contrary to
their claims, established HIV as a passenger virus of AIDS patients.
(3) 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 that there is no antiviral immunity.
This is because 100 viruses infect 100 cells producing 100x100 or
10,000 viruses 2 days later. Within 14 days of such exponential
growth 10^14 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 .
Since HIV replicates in 2 days, like all other retroviruses ,
and since according to Ho an infected cell produces over 1000 viruses
per 2 days , 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 10^5 "free viruses/virions" and 10^5 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-timies 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 10^3 "plasma viral RNA" units to 10^5
units per ml described by Wei et. al. should only be a fraction
of the real "dynamics of the infection in people by HIV"
, 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
remains paradoxical that-dated from the time of HIV infection-AIDS
occurs at entirely unpredictable times, currently estimated to average
10 years . 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.
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 viurs is that
its titer and even its presence are not correlated with disease-
just as was shown above form HIV and AIDS.
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
. Take for example the slow decline of liver cells in long-term
alcoholics or of lung cells in long-term smokers.
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 obvous failures and inconsistencies: Why is there no vaccine?
Why does American/European AIDS stay in the classical risk groups,
male homosexual, 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?
 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?  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?  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? 
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 nitrate inhalants, amphetamines,
and cocaine are immunotoxic or carcinogenic?  Why is it that
among 10 long-term (10 to15 years) survivors of HIV recently described
by Ho et. al.  "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 assoiated
with zidovudine [AZT] administration from underlying signs of HIV
diseases..."?  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
are typed in the following manner: 10 to the power of 4 appears
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.
 Wei, X.,
et. al., _Nature_ 373, p. 117-122 (1995)
 Ho, D.D.,
et al., _Nature_ 373, p. 123-126 (1995)
J. _Nature_ 373, 189, p. 189 (1995)
R.C., et. al., _Science_ 224, p. 500-503 (1984)
of Medicine, _Confronting AIDS- Update 1988_ (National Academy Press,
Washington DC, 1988)
for Disease Control and Prevention, _Morb Mort Weekly Rep_ 41(No.
RR17), p. 1-19 (1992)
P.H., _Pharmacology & Therapeutics_ 55, p. 201-277 (1992) 
Duesberg, P.H., _Int. Arch. Allergy Immunol_ 103, p. 131-142 
Murray, H.W., Scavuzzo, D.A., Kelly, C.D., Rubin, B.Y. & Roberts,
R.B._Arch. Intern. Med._ 148, p. 1613-1616 (1988)
P., et.al., _Br. J. Dermatol_ 335, p. 1-9 (1988)
A.E., et.al., _Lancet_ 335, p. 168-169 (1990)
J.M., Tindall, B., Williamson, P. Elford, J & Cooper, D.A.,
_Journal of Acquired Immune Deficiency Syndromes_ 6, p. 1145-1149
H., et.al, _Neurology_ 44, p. 1892-1900 (1994)
W.A., Gallo, R.C. & Tein, H.M. _Science_ 241, p. 514-515 (1988)
P.H. _Science_ 241, p. 514-516 (1988)
M. et al., _Science_ 259, p. 1749-1754 (1993)
E.S., Moudgil, T., Meyer, R.D. & Ho, D.D. _N. Eng. J. Med._
324, p. 961-964 (1991)
S.J., et.al. _N. Engl. J. Med._ 324, p. 954-960 (1991)
P.H. _Science_ 260, p. 1705 (1993)
C. & White, D.O. _Viral Pathogenesis and Immunology_ (Blackwell
Scientific Publications, Oxford, 1984)
B.A. _Burrows Textbook of Microbiology_ (W.B. Saunders Co., Philadeophia,
R.A. _Science_ 260, p. 1273-1279
F., McAuslan, B.R., Mims, C.A., Sambrook, J. & White, D.O. _The
Biology of Animal Viruses_ (Academic Press, Inc., New York, 1974)
L _Oncogenic Viruses_ (Pergamon Press, Oxford, 1970)
M.E., Marselle, L.M., Gallo, R.C. & Wong-Staal, F. _PNAS_ 83,
p. 772-776 (1986)
P., et.al. _J. Virol._ 64, P. 864-872 (1990)
G.M., et. al. _Science_ 226, p. 1165-1171 (1984)
S.H., et. al., Science_ 239, p. 68-71 (1988)
L.A., Jr. _NEJM_ 316, p. 1547-1548 (1987)
 Ho, D.D.,
Moudgil, T. & Alam, M _New Engl. J. Med_ 321, p. 1621-1625 (1989)
S.M., et.al. _Science_ 245, p. 305-308 (1989)
 Ho, D.
_New Engl. J. Med_ 322, p. 1467 (1990)
for Disease Control _HIV/AIDS Surveillance_, Year-end edition, p.
J. & Jasny, B. _Science_ 260, p. 1219, 1253-1293 (1993)
B.N. _Nature_ 369, p. 95-96 (1994)
D. _Nature_ 370, p. 494 (1994)
E. _Science_ 248, p. 1499-1507 (1990)
A., Lowdell, M., Jacobson, S.K., & Hill, F _PNAS_ 89, p. 8351-8355
E., et.al., _J. Clin. Invest._ 84, p. 1637-1643 (1989)
M., Guetard, D., Henin, Y., Montagnier, L. & Zerial, A., _Res.
Virol_ 141, p. 5-16 (1990)
J.A., Haggarty, B.S., Rakowski, J.L., Pillsbury, N. & Levy,
J.A., _Science_ 229, p. 1400-1402 (1985)
R., et.al., _Lancet_ ii, p. 234-238
S. _Nature_ 373, (1995)
G., et.al. _Nature_ 362, p. 355-358 (1993)
J. _Science_ 259, p. 168-170 (1993)
R. _Nature_ 349, p. 374 (1991)
J., et.al. _Nature_ 362, p. 359-352 (1993)
R., Teich, N., Varmus, H. & Coffin, J. _Molecular Biology of
RNA Tumor Viruses (Cold Spring Harbor Press, Cold Spring Harbor,
J. _Scince_ 260, p. 292-293 (1993)
 Cao, Y.,
Quin, L., Zhang, L., Safrit, J. & Ho, D.D. _N Engl. J. Med_
332, p. 201-208 (1995)
L. _Analytical Biochemistry_ 214, p. 582-585 (1993)
 Ho, D.D.,
et.al. _NEJM_ 328, p. 380-385 (1993)
P.H. _Science_ 260, p. 1705 (1993)
P.H. _N. Engl. J. Med_ 322, p. 1466 (1990)
M., et.al., _Lancet_ 343, p. 871-881 (1994)
J.J., et.al. _Lancet_ 344, p. 791-792 (1994)
J. _Capital Gay_ August 20, p. 14-15 (1993)
M.D., et.al. _J. Infectious Diseases_ 169, p. 28-36 (1994)
S.V., et.al. _Lancet_ 342, p. 700-703 (1993)
P.H. _Science_ 267, p. 313 (1995)
H.W. & Dougherty, J.A. _Health Hazards of Nitrite Inhalants_(U.S.
Dept. of Health & Human Services, Washington DC, 1988)
Desk Reference, _Retrovir_ p. 742-746 (Medical Economics Co., Orandell,