Progress in Nucleic Acid Research and Molecular Biology
43:135-204, 1992

Latent Viruses and Mutated
Oncogenes: No Evidence
for Pathogenicity


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 (3).

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 Hypotheses

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 proven guilty.

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.