Retroviruses as Carcinogens and Pathogens: Expectations and Reality
by Peter H. Duesberg
Department of Molecular Biology and Virus Laboratory, UC Berkeley
[Reproduced here by express permission of both the author and
the publisher, Cancer Research, March 1, 1987 -- sysop]
Abstract
Retroviruses (without transforming genes) are thought to cause
leukemias and other cancers in animals and humans because they were
originally isolated from those diseases and because experimental
infections of newborns may induce leukemias with probabilities of
0 to 90%. According to this hypothesis viral cancers should be
contagious, polyclonal, and preventable by immunization. However,
retroviruses are rather widespread in healthy animals and humans
where they typically cause latent infections and antiviral immunity.
The leukemia risk of such infections is less than 0.1% and thus about
as low as that of virus-free controls. Indeed retroviruses are not
sufficient to initiate transformation (a) because of the low percentage
of symptomatic virus carriers and the complete lack of transforming
function in vitro; (b) because of the striking discrepancies between
the long latent periods of 0.5 to 10 years for carcinogenesis and
the short eclipse of days to weeks for virus replication and direct
pathogenic and immunogenic effects; (c) because there is no gene with
a late transforming function, since all genes are essential for
replication; (d) because host genes, which do not inhibit virus,
inhibit tumorigenesis up to 100% if intact and determine the nature
of the tumor if defective; and above all (e) because of the monoclonal
origin of viral leukemias, defined by viral integration sites that
are different in each tumor. On these bases the probability that a
virus-infected cell will become transformed is estimated to be about
10 (11th power). The viruses are also not necessary to maintain
transformation, since many animal and all bovine and human tumors do
not express viral antigens or RNA or contain only incomplete
proviruses. Thus as carcinogens retroviruses do not or only very
rarely (10 (11th power)) fulfill the third. Therefore it has been
proposed that retroviruses transform inefficiently by activating
latent cellular oncogenes by for example provirus integration. This
predicts diploid tumors with great diversity, because integration
sites are different in each tumor. However, the uniformity of
different viral and even nonviral tumors of the same lineage, their
common susceptibility to the same tumor resistance genes, and
transformation-specific chromosome abnormalities shared with
nonviral tumors each argue for cellular transforming genes. Indeed
clonal chromosome abnormalities are the only known transformation-
specific determinants of viral tumors. Since tumors originate with
these abnormalities, these or associated events, rather than
preexisting viruses, must initiate transformation. Therefore it is
proposed that transformation is a virus-independent event and that
clonal viral integration sites are consequences of clonal
proliferation of transformed cells. The role of the virus in
carcinogenesis is limited to the induction of hyperplasia which is
necessary but not sufficient for carcinogenesis. Hyperplasia
depends on chronic viremia or high virus expression which are very
rare in animals outside the laboratory and have never been observed
in humans. Since latent viruses, which are typical of nearly all
natural infections, are neither direct nor indirect carcinogens,
they are not targets for cancer prevention. Viruses are also not
targets for cancer therapy, since tumors are not maintained and
not directly initiated by viral genes and occur naturally despite
active antiviral immunity.
Lymphotropic retrovirus has been proposed to cause AIDS because
90% of the patients have antibody to the virus. Therefore antibody
to the virus is used to diagnose AIDS and those at risk for AIDS.
The virus has also been suggested as a cause of diseases of the
lung and the nervous system. Promiscuous male homosexuals and
recipients of frequent transfusions are at high risk for infection
and also at a relatively high risk for AIDS, which averages 0.3%
and may reach 5%. Others are at a low risk for infection and if
infected are at no risk for AIDS. AIDS viruses are thought to
kill T-cells, although these viruses depend on mitosis for
replication and do not lyse cells in asymptomatic infections.
Indeed the virus is not sufficient to cause AIDS (a) because the
percentage of symptomatic carriers is low and varies between 0
and 5% with the risk group of the carrier, suggesting a cofactor
or another cause; (b) because the latent period for AIDS is 5
years compared to an eclipse of only days to weeks for replication
and direct pathogenic and immunogenic effects; and (c) because
there is no gene with a late AIDS function, since all viral genes
are essential for replication. Moreover the extremely low levels
of virus expression and infiltration cast doubt on whether the
virus is even necessary to cause AIDS or any of the other diseases
with which it is associated. Typically, proviral DNA is
detectable in only 15% of AIDS patients and then only in one of
10 (2nd power) to 10 (3rd power) lymphocytes and is expressed in
only 1 of 10 (4th power) to 10 (5th power) lymphocytes. Thus the
virus is inactive or latent in carriers with and without AIDS.
It is for this reason that it is not transmitted as a cell-free
agent. By contrast, all other viruses are expressed at high
titers when they function as pathogens. Therefore AIDS virus
could be just the most common occupational infection of those at
risk for AIDS because retroviruses are not cytocidal and unlike
most viruses persist as latent, nonpathogenic infections. As
such the virus is an indicator of sera that may cause AIDS.
Vaccination is not likely to benefit virus carriers, because
nearly all have active antiviral immunity.
Published at the AIDS AUTHORITY web site; reprinted with permission