Progress in Nucleic Acid Research and Molecular Biology
Latent Viruses and Mutated
Oncogenes: No Evidence
H. DUESBERG AND
Department of Molecular and Cell Biology
University of California at Berkeley
Berkeley, California 94720
I. New Technology
and Old Theories in the Search for the Causes of Disease
A. A New Generation of Virologists Presents
Latent Viruses as Pathogens
Although viral epidemics have all but disappeared in the Western world
since polio was eliminated with vaccines in the 1950s, the number of viruses
currently discovered and studied by virologists has reached epidemic proportions.
For example, zealous virus hunters have been able to detect by ultrasensitive
biological and biotechnical methods latent viruses that are neutralized
by antiviral immunity in diseases such as AIDS, leukemias, lymphomas, hepatomas,
hepatitis, cervical cancers, encephalitis, and many others (1,3). Their
proposals that latent viruses cause these diseases are widely accepted,
because from the days when only the most pathogenic and abundant viruses
were detectable, all viruses still have the reputation of being pathogens.
However, the diseases with which these newly discovered
latent viruses are associated are not contagious-unless one makes bizarre
assumptions. One assumption postulates that these viruses are "slow
viruses" or "lentiviruses" causing diseases only up to 55
years after infection and only after they are neutralized by antibodies
(see Sections II and III). Yet all of these viruses replicate and are immunogenic
within weeks, not years, after infection just like conventional viruses.
Another assumption is that these viruses can shift from a nonpathogenic
dormant state to a pathogenic state without increasing their biochemical
activity or abundance.
A case in point is the assumption that AIDS is caused
by a virus. There were over 160,000 AIDS patients in the U.S. in the last
10 years, and there is no antiviral vaccine or drug. Yet at the time of
this writing there is not even one confirmed case of a health care worker
who contracted AIDS from a patient, nor of a scientist who contracted AIDS
from the "AIDS virus" that is propagated in hundreds of research
laboratories! The AIDS virus is just as inactive in patients as it is in
asymptomatic virus carriers (see Section II).
Such assumptions are not compatible with classical criteria
of viral pathogenicity. Conventional viruses are very active, abundant
and replicating in many cells that are killed or transformed when they
cause diseases such as polio, flu, measles, mumps, hepatitis, herpes, Rous
sarcoma, and many others (3, 10-12). Likewise, SV40 and adenoviruses inundate
many cells with viral T-antigens when they cause tumors, even though the
respective host animals are not permissive for viral replication (13).
Pathogenicity by these classical viruses results from high biochemical
activity in large numbers of cells. These viruses are not pathogenic when
they are latent or infect only small numbers of cells. Indeed, even the
most pathogenic viruses depend for their survival on asymptomatic infections
in which they are highly active in small numbers of cells before they are
stopped by antiviral immunity, the reason that such infections are asymptomatic
Furthermore, all conventional viruses are maximally pathogenic
within weeks or months after infection before they are neutralized by antiviral
immunity, causing disease as soon as they reach pathogenic thresholds in
the host (10-12). In rare cases, they may be reactivated to resume replication,
and hence pathogenicity, long after they are neutralized by antiviral immunity
(e.g., the herpes simplex virus). Reactivation typically follows a transient
immunodeficiency acquired by another primary disease or other immunosuppressive
conditions (12). Except for these instances of viral reactivation, there
are no known examples of viruses that cause diseases only after a long
latent period and only after they have been neutralized by antibodies.
Thus, the evidence that latent viruses can be pathogenic
is only circumstantial, based on structural similarities between latent
viruses and active, pathogenic viral prototypes. Further, these hypotheses
are based on the epidemiological evidence that latent viruses occur, or
appear to occur, in diseases at a higher rate than would be expected from
random infection (3, 14, 15) (see Section V).
B. From Retroviral to Cellular
Oncogenes-The Oncogene Hypothesis
New technology detecting point-mutations, deletions, and
truncations of cellular genes and latent or defective viruses put new life
in the somatic mutation hypothesis of cancer (16). It was postulated in
1969 by Huebner and Todaro that latent viruses and covert cancer genes
preexist in normal cells and are "activated" to cancer genes
and cancer viruses by mutation (17). The proposal became known as the oncogene
hypothesis. The discoveries in 1970 of retroviral oncogenes (18, 19) and
in 1973 of cellular genes from which the coding regions of retroviral oncogenes
are derived (20-22) put the oncogene hypothesis to its first test. It was
proposed that mutation turns those genes from which the coding regions
of retroviral oncogenes are derived into equivalents of viral oncogenes
(6). These genes are now called either proto-onc genes or cellular
oncogenes (1, 5-8, 23, 24) or even "enemies within" the cell
(25). And mutated cellular oncogenes are euphemistically termed "activated"
cellular oncogenes (1, 5-8).
Examples of "activated" oncogenes are point-mutated
proto-ras genes that are thought to be bladder or colon cancer genes
(23, 26-28), truncated proto-myc genes that are thought to be Burkitt's
lymphoma genes (29, 30), proto-myc genes with retroviruses integrated
upstream (31) and downstream (32) that are thought to be avian lymphoma
genes, and rearranged proto-abl genes that are thought to be myelogenous
leukemia genes (7, 8, 33). By analogy to proto-onc genes, even genes
that are not related to retroviral onc genes are now thought to
be "activated" oncogenes if mutated by provirus integration,
like the int genes of mouse mammary tumors with retroviruses integrated
within or nearby (5, 8, 34).
However, mutated proto-onc genes and int
genes with integrated retroviruses are either just as active or only slightly
more active than their normal counterparts (see Section IV). Moreover,
the mutant genes from tumors do not transform cells upon transfection.
By contrast, proviral DNA copies of retroviral oncogenes transform susceptible
cells and are about 100 times more active than normal proto-onc
genes (24, 35-38). During the last 5 years, the transforming function of
retroviral oncogenes, including those of Rous sarcoma, Harvey sarcoma,
and MC29 and MH2 carcinoma viruses, has been shown to depend absolutely
on transcriptional activity, rather than on mutations in the coding region
(39-44). This high transcriptional activity of retroviral oncogenes results
from retroviral promoters.
The latest modification of the oncogene hypothesis, the
antioncogene hypothesis, proposes that constitutively active, but as yet
unnamed, oncogenes are "activated" by mutational inactivation
of tumor suppressors or anti-oncogenes (8, 9, 45). Examples are the retinoblastoma
and p53 anti-oncogenes that are thought to cause retinoblastoma (45) and
colon cancer (46) if they are inactivated by point-mutation, truncation,
or deletion. However, unmutated antioncogenes do not revert tumor cells
to normal (see Section IV).
Thus, the evidence for these hypotheses is only circumstantial,
based on structural similarities between mutated "cellular oncogenes"
displaying a normal level of activity and about 100 times more active viral
oncogenes. Further, these hypotheses are based on the epidemiological evidence
that mutated genes occur, or appear to occur, in diseases at a much higher
rate than would be expected from spontaneous mutation (4, 5, 7, 28, 47)
(see Section V).
C. From Autonomous Pathogens
to Multifactorial Causes of Disease
In view of the apparent non-equivalence between the postulated
pathogens and their prototypes, the original hypotheses have been supplemented
by ad hoc hypotheses. Typically, these ad hoc hypotheses
postulate second- or even higher-order mechanisms of pathogenesis that
include cofactors and helper genes, in contrast to the classical prototypes,
which all follow first-order mechanisms of pathogenesis. Moreover, the
putative helper genes, like the putative primary pathogens, are not disease-specific,
because they are also found in asymptomatic subjects. Indeed, "cofactors"
are euphemisms for new hypotheses, which grant face-saving roles to failing
incumbents with large constituencies.
D. The Search for Alternative
In the following, we have reinvestigated the evidence
for the claims that latent viruses and mutated genes are pathogenic. Since
the available evidence for pathogenicity is insufficient, we conclude that
the latent viruses and mutated genes must be considered innocent until
Since falsification creates a vacuum, we have attempted
to present brief alternatives, drawing in most cases from published work.
However, in the case of AIDS, we have documented an alternative to the
virus-AIDS hypothesis more extensively, because there is hardly any mention
of alternatives in the over 60,000 papers published on the AIDS virus and
AIDS since 1983 (48). By challenging currently unproductive hypotheses
and by providing falsifiable alternatives, we hope to contribute to the
search for what really causes these diseases.