Simian virus 40 infection in humans and association with human diseases: results and hypotheses

Abstract

Simian virus 40 (SV40) is a monkey virus that was introduced in the human population by contaminated poliovaccines, produced in SV40-infected monkey cells, between 1955 and 1963. Epidemiological evidence now suggests that SV40 may be contagiously transmitted in humans by horizontal infection, independent of the earlier administration of SV40-contaminated poliovaccines. This evidence includes detection of SV40 DNA sequences in human tissues and of SV40 antibodies in human sera, as well as rescue of infectious SV40 from a human tumor. Detection of SV40 DNA sequences in blood and sperm and of SV40 virions in sewage points to the hematic, sexual, and orofecal routes as means of virus transmission in humans. The site of latent infection in humans is not known, but the presence of SV40 in urine suggests the kidney as a possible site of latency, as it occurs in the natural monkey host. SV40 in humans is associated with inflammatory kidney diseases and with specific tumor types: mesothelioma, lymphoma, brain, and bone. These human tumors correspond to the neoplasms that are induced by SV40 experimental inoculation in rodents and by generation of transgenic mice with the SV40 early region gene directed by its own early promoter-enhancer. The mechanisms of SV40 tumorigenesis in humans are related to the properties of the two viral oncoproteins, the large T antigen (Tag) and the small t antigen (tag). Tag acts mainly by blocking the functions of p53 and RB tumor suppressor proteins, as well as by inducing chromosomal aberrations in the host cell. These chromosome alterations may hit genes important in oncogenesis and generate genetic instability in tumor cells. The clastogenic activity of Tag, which fixes the chromosome damage in the infected cells, may explain the low viral load in SV40-positive human tumors and the observation that Tag is expressed only in a fraction of tumor cells. "Hit and run" seems the most plausible mechanism to support this situation. The small tag, like large Tag, displays several functions, but its principal role in transformation is to bind the protein phosphatase PP2A. This leads to constitutive activation of the Wnt pathway, resulting in continuous cell proliferation. The possibility that SV40 is implicated as a cofactor in the etiology of some human tumors has stimulated the preparation of a vaccine against the large Tag. Such a vaccine may represent in the future a useful immunoprophylactic and immunotherapeutic intervention against human tumors associated with SV40.

High prevalence of serum antibodies reacting with simian virus 40 capsid protein mimotopes in patients affected by malignant pleural mesothelioma

“…The high prevalence of SV40 antibodies in serum samples from MPM patients seems to confirm earlier data obtained in investigations carried out with PCR techniques, which indicated a high prevalence of SV40 sequences in MPM DNA (13,20). Data obtained in normal individuals suggest that natural SV40 infection occurs in human populations with a prevalence lower than that of the ubiquitous JCV and BKV (60-90%) (25).…”

“…Although asbestos is considered the main cause, SV40 may be an additional candidate for causing mutations and chromosome alterations in tumors. SV40 was found to be mutagenic in human cells (20,31). The viral oncoprotein Tag induces mutations and chromosomal damage characterized by numerical and structural chromosomal alterations such as gaps, breaks, dicentric and ring chromosomes, chromatid exchanges, deletions, duplications, and translocations (20).…”

“…Contrasting reports have appeared in the literature on the presence of SV40 footprints in humans and its association with human tumors (20)(21)(22). SV40 antibody detection had been attempted in several studies using serologic methods with SV40 virus-like particles (VLPs), but because of high protein homology among the three main polyomaviruses SV40, BKV, and JCV, the results were always affected by some cross-reactivity (23)(24)(25)(26)(27)(28)(29)(30).…”

Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins

“…The natural host of SV40 is the monkey Macacus Rhesus, but even if SV40 usually does not infect humans, accidental injection of SV40 has been reported in people taking the injected form of the polio vaccine between the years 1955 and 1963 (Rizzo et al, 1999;Jasani et al, 2001;Barbanti-Brodano et al, 2004;Dang-Tan et al, 2004). On the other hand, long-term epidemiology studies have failed to detect an increased cancer risk in those individuals likely to have been exposed to the virus mainly by SV40-contaminated polio vaccines (Mortimer et al, 1981;Strickler et al, 1998).…”

Anticancer activity of an adenoviral vector expressing short hairpin RNA against BK virus T-ag

“…Other viral oncogenes could be targeted by this approach. For instance the highly homologous SV40 T-ag model system, whose association with human neoplasms has been reported by several investigators, 42 or the viral oncogenes associated with the human oncogenic papillomaviruses. Indeed, suppression of E6 expressed by HPV-16 or HPV-18 in human cell lines resulted in apoptotic cell death and in suppression of tumorigenicity.…”