Simian virus 40 transformation, malignant mesothelioma and brain tumors

Abstract

Simian virus 40 (SV40) is a DNA virus isolated in 1960 from contaminated polio vaccines, that induces mesotheliomas, lymphomas, brain and bone tumors, and sarcomas, including osteosarcomas, in hamsters. These same tumor types have been found to contain SV40 DNA and proteins in humans. Mesotheliomas and brain tumors are the two tumor types that have been most consistently associated with SV40, and the range of positivity has varied about from 6 to 60%, although a few reported 100% of positivity and a few reported 0%. It appears unlikely that SV40 infection alone is sufficient to cause human malignancy, as we did not observe an epidemic of cancers following the administration of SV40-contaminated vaccines. However, it seems possible that SV40 may act as a cofactor in the pathogenesis of some tumors. In vitro and animal experiments showing cocarcinogenicity between SV40 and asbestos support this hypothesis.

Figure 1. Structure and function of simian virus 40

(A) Physical and functional map of the SV40 genome. The circular DNA genome is 5243 bp. Ori (black). Tag, tag and 17KT (black): ‘Early gene’ mRNAs, controlled by the pE (blue). pL (blue) shares the same sequence with pE, but is oriented in the opposite direction. VP1, VP2, VP3, VP4 and Agno (blue): transcripts of ‘late genes’, are under control of pL and encode capsid proteins VP1, VP2, VP3, and VP4 and Agnoprotein assembly promoting proteins. VP2-4 share the same stop codon. (B) SV40 early proteins: Tag, 17KT and tag share the first 82 amino acid residues at the N-terminal (gray). Tag extends up to 708 residues in length (blue), but skips the tag encoding region (black), owing to differential splicing. 17KT encodes a 135 amino acids protein, sharing the first 131 residues (gray and blue) with Tag, followed by four amino acids encoded by the third intron of the Tag gene, retained by an alternative splicing. SV40 tag is a 174 residue protein. Ori: Origin of viral DNA replication; pE: Early promoter; pL: Late promoter; SV40: Simian virus 40; Tag: Large T antigen; tag: Small t antigen.

Figure 2. Silencing mechanism of simian virus 40 late gene transcription

Early genes transcripts extend beyond poly A signal and overlap the late gene region (light gray), leading to late gene antisense RNA. The resulting double-strand RNA is degraded, impairing late gene expression. EP: Early promoter; gDNA: Genomic DNA; LP: Late promoter.

Figure 3. Mechanisms of simian virus 40 infection and cell transformation

Upon SV40 entry, Tag is expressed and accumulates in the host cells, where it binds to p53, pRb, p300, p400 and possibly other proteins, to form a multiprotein complex that activates transcription of IGF-1. Tag also induces, possibly with similar mechanisms, the expression of other growth factors. (A) In the majority of infected HM, late gene transcription leads to VP1-3 viral capsid protein expression and virion assembly. Host cells undergo necrotic lysis, owing to massive viral release and a PARP-mediated mechanism. (B) In a fraction of infected HM, VP1-3 expression is blocked by the antisense mechanism [35], virions are neither assembled nor released and host cells survive. (C) In these cells, the signaling induced by the autocrine IGF-1/IGF-1R loop (and by other ligand/receptor autocrine circuits) eventually leads to G1/S progression and cell proliferation. Also tag contributes to cell survival inducing Akt activity as a consequence of PP2A inhibition. (D) Exposure to asbestos activates EGFR signaling, leading to ERK activity and AP-1 transcription, and induces programmed cell necrosis with consequent release of HMGB1 and other proinflammatory cytokines [77], leading to chronic inflammation. (E) The signaling induced by asbestos and SV40 infection, either independently or in a cooperative manner, can promote HM transformation and mesothelioma development. EGFR: EGF receptor; HM: Human primary mesothelial cell; HMGB1: High molecular group binding protein 1; PARP: Poly (ADP-ribose) polymerase; pRb: Retinoblastoma protein; SV40: Simian virus 40; Tag: Large T antigen; tag: Small t antigen; VEGFR: VEGF receptor.