SV40 is an abbreviation for simian vacuolating virus 40orsimian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that sometimes causes tumors in animals, but most often persists as a latent infection. SV40 has been widely studied as a model eukaryotic virus, leading to many early discoveries in eukaryotic DNA replication[1] and transcription.[2]
Following contamination of polio vaccine batches in the 1950s and 1960s, SV40 came under suspicion as a possible cancer risk, but no subsequent increased cancer rate was observed, making such a risk unlikely. Nevertheless SV40 has become a cause célèbre for anti-vaccination activists, who have blamed it for multiple ills, including cancer and HIV/AIDS.[3]
The hypothesis that SV40 might cause cancer in humans was a particularly controversial area of research, fuelled by the historical contamination of some batches of polio vaccine with SV40 in the 1950s and 1960s.[4] "Persuasive evidence now indicates that SV40 is causing infections in humans today and represents an emerging pathogen."[5] However "It appears unlikely that SV40 infection alone is sufficient to cause human malignancy..."[6]
Some vaccines made in the US between 1955 and 1961 were found to be contaminated with SV40, from the growth medium and from the original seed strain. Population level studies did not show extensive evidence of increase in cancer incidence as a result of exposure,[9] though SV40 has been extensively studied.[10] A thirty-five year follow-up did not find excess numbers of cancers associated with SV40.[11]
SV40 consists of an unenvelopedicosahedralvirion with a closed circular double-stranded DNA genome[15] of 5.2 kb.[16] The virion adheres to cell surface receptors of MHC class I by the virion glycoprotein VP1. Penetration into the cell is through a caveolinvesicle. Inside the cell nucleus, the cellular RNA polymerase II acts to promote early gene expression. This results in an mRNA that is spliced into two segments. The small and large T antigens result from this. The large T antigen has two functions: 5% goes to the plasma cell membrane and 95% returns to the nucleus. Once in the nucleus the large T antigen binds three viral DNA sites, I, II and III. Binding of sites I and II autoregulates early RNA synthesis. Binding to site II takes place in each cell cycle. Binding site I initiates DNA replication at the origin of replication. Early transcription gives two spliced RNAs that are both 19s. Late transcription gives both a longer 16s, which synthesizes the major viral capsid protein VP1; and the smaller 19s, which gives VP2 and VP3 through leaky scanning. All of the proteins, besides the 5% of large T, return to the nucleus because assembly of the viral particle happens there. A putative late protein VP4 has been reported to act as a viroporin facilitiating release of viral particles and resulting in cytolysis;[17][18] however the presence and role of VP4 have been disputed.[19][20]
SV40 is capable of multiplicity reactivation (MR).[21][22] MR is the process by which two or more virus genomes containing otherwise lethal damage interact within an infected cell to form a viable virus genome. Yamamato and Shimojo observed MR when SV40 virions were irradiated with UV light and allowed to undergo multiple infection of host cells.[21] Hall studied MR when SV 40 virions were exposed to the DNA crosslinking agent 4, 5', 8-trimethylpsoralen.[22] Under conditions in which only a single virus particle entered each host cell, approximately one DNA cross-link was lethal to the virus and could not be repaired. In contrast, when multiple viral genomes infected a host cell, psoralen-induced DNA cross-links were repaired; that is, MR occurred. Hall suggested that the virions with cross-linked DNA were repaired by recombinational repair.[22] Michod et al. reviewed numerous examples of MR in different viruses and suggested that MR is a common form of sexual interaction that provides the advantage of recombinational repair of genome damages.[23]
The early promoter for SV40 contains three elements. The TATA box is located approximately 20 base-pairs upstream from the transcriptional start site. The 21 base-pair repeats contain six GC boxes and are the site that determines the direction of transcription. Also, the 72 base-pair repeats are transcriptional enhancers. When the SP1 protein interacts with the 21 base-pair repeats, it binds either the first or the last three GC boxes. Binding the first three initiates early expression, binding the last three initiates late expression. The function of the 72 base-pair repeats is to enhance the amount of stable RNA and increase the rate of synthesis. This is done by binding (dimerization) with the AP-1 transcription factor to give a primary transcript that is 3' polyadenylated and 5' capped.[citation needed]
The molecular mechanisms by which the virus reproduces and alters cell function were previously unknown, and research into SV40 vastly increased biologists' understanding of gene expression and the regulation of cell growth.[citation needed]
SV40 has become a totemic subject among anti-vaccination activists, where its presence in contaminated vaccine is accused of being a cause of a cancer "epidemic" and of being responsible for HIV/AIDS.[3]
^Poulin, D. L.; Decaprio, J. A. (2006). "Is There a Role for SV40 in Human Cancer?". Journal of Clinical Oncology. 24 (26): 4356–65. doi:10.1200/JCO.2005.03.7101. PMID16963733.
^Hilleman MR (1998). "Discovery of simian virus 40 (SV40) and its relationship to poliomyelitis virus vaccines". Dev Biol Stand. 94: 183–90. PMID9776239.
^ abYamamoto, Hiroshi; Shimojo, H (August 1971). "Multiplicity reactivation of human adenovirus type 12 and simian virus 40 irradiated by ultraviolet light". Virology. 45 (2): 529–31. doi:10.1016/0042-6822(71)90355-2. PMID4328814.
^ abcHall, J. D. (1982). "Repair of psoralen-induced crosslinks in cells multiply infected with SV40". Molecular & General Genetics. 188 (1): 135–8. doi:10.1007/bf00333007. PMID6294477. S2CID5843939.
^Sweet, B. H.; Hilleman, M. R. (November 1960). "The vacuolating virus, S.V. 40". Proceedings of the Society for Experimental Biology and Medicine. 105 (2): 420–427. doi:10.3181/00379727-105-26128. PMID13774265. S2CID38744505.
^Eddy, B. E.; Borman, G. S.; Grubbs, G. E.; Young, R. D. (May 1962). "Identification of the oncogenic substance in rhesus monkey kidney cell culture as simian virus 40". Virology. 17: 65–75. doi:10.1016/0042-6822(62)90082-x. PMID13889129.