|Other names||Simian vacuolating virus 40, simian virus 40|
SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that has the potential to cause 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 and transcription.
The hypothesis that SV40 might cause cancer in humans has been a particularly controversial area of research. It is currently unclear whether SV40 has any role in causing tumors. As a result of these uncertainties, academic opinion remains divided, with some arguing that this hypothesis is not supported by the data and others arguing that some cancers may involve SV40. The US National Cancer Institute announced in 2004 that although SV40 does cause cancer in some animal models, "substantial epidemiological evidence has accumulated to indicate that SV40 likely does not cause cancer in humans". This announcement was based on two studies. This 2004 announcement is in contrast to a 2002 study performed by The National Academy of Sciences Immunization Safety Review committee that stated, "The committee concludes that the biological evidence is moderate that SV40 exposure could lead to cancer in humans under natural conditions".
p53 damage and carcinogenicity
SV40 may act as a co-carcinogen with crocidolite asbestos to cause mesothelioma. The mechanism may involve suppression of the transcriptional properties of tumor suppressor p53 in humans by the SV40 large T antigen and SV40 small T-antigen. Tumor suppressor p53 is responsible for initiating regulated cell death ("apoptosis"), or cell cycle arrest when a cell is damaged. A mutated p53 gene may contribute to uncontrolled cellular proliferation, leading to a tumor.
Polio vaccine contamination
Some vaccines made in the USA 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, though SV40 has been extensively studied. A thirty-five year follow-up did not find excess numbers of cancers associated with SV40.
|Simian virus 40|
Simian virus 40
SV40 consists of an unenveloped icosahedral virion with a closed circular double-stranded DNA genome of 5.2 kb. The virion adheres to cell surface receptors of MHC class I by the virion glycoprotein VP1. Penetration into the cell is through a caveolin vesicle. 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; however the presence and role of VP4 have been disputed.
SV40 is capable of multiplicity reactivation (MR). 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. Hall studied MR when SV 40 virions were exposed to the DNA crosslinking agent 4, 5', 8-trimethylpsoralen. 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. 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.
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.
SV40 is dormant and is asymptomatic in rhesus monkeys. The virus has been found in many macaque populations in the wild, where it rarely causes disease. However, in monkeys that are immunodeficient—due to, for example, infection with simian immunodeficiency virus—SV40 acts much like the human JC and BK polyomaviruses, producing kidney disease and sometimes a demyelinating disease similar to progressive multifocal leukoencephalopathy. In other species, particularly hamsters, SV40 causes a variety of tumors, generally sarcomas. In rats, the oncogenic SV40 large T antigen was used to establish a brain tumor model for primitive neuroectodermal tumor and medulloblastoma.
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.
SV40 was first identified by Ben Sweet and Maurice Hilleman in 1960 when they found that between 10 and 30% of polio vaccines in the USA were contaminated with SV40. In 1962, Bernice Eddy described the SV40 oncogenic function inducing sarcoma and ependymomas in hamsters inoculated with monkeys cells infected with SV40. The complete viral genome was sequenced by Weissman at Yale University (USA) in 1978 and also by Fiers and his team at the University of Ghent (Belgium).
- Fanning, E; Zhao, K (February 2009). "SV40 DNA replication: From the A gene to a nanomachine". Virology. 384 (2): 352–359. doi:10.1016/j.virol.2008.11.038. PMC 2718763. PMID 19101707.
- Banerji, J; Rusconi, S; Schaffner, W (December 1981). "Expression of a β-globin gene is enhanced by remote SV40 DNA sequences". Cell. 27 (2): 299–308. doi:10.1016/0092-8674(81)90413-X. PMID 6277502. S2CID 54234674.
- 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. PMID 16963733.
- Lowe, D. B.; Shearer, M. H.; Jumper, C. A.; Kennedy, R. C. (2007). "SV40 association with human malignancies and mechanisms of tumor immunity by large tumor antigen". Cellular and Molecular Life Sciences. 64 (7–8): 803–14. doi:10.1007/s00018-007-6414-6. PMID 17260087. S2CID 12994993.
- Shah, K. V. (2007). "SV40 and human cancer: A review of recent data". International Journal of Cancer. 120 (2): 215–23. doi:10.1002/ijc.22425. PMID 17131333. S2CID 20679358.
- Moens, U; Van Ghelue, M; Johannessen, M (2007). "Oncogenic potentials of the human polyomavirus regulatory proteins". Cellular and Molecular Life Sciences. 64 (13): 1656–78. doi:10.1007/s00018-007-7020-3. PMID 17483871. S2CID 31314244.
- Barbanti-Brodano, G; Sabbioni, S; Martini, F; Negrini, M; Corallini, A; Tognon, M (2004). "Simian virus 40 infection in humans and association with human diseases: results and hypotheses". Virology. 318 (1): 1–9. doi:10.1016/j.virol.2003.09.004. PMID 15015494.
- "Studies Find No Evidence That SV40 is Related to Human Cancer". National Cancer Institute, National Institutes of Health. 23 August 2004. Archived from the original on 28 October 2014.
- Engels, E. A.; Chen, J; Hartge, P; Cerhan, J. R.; Davis, S; Severson, R. K.; Cozen, W; Viscidi, R. P. (2005). "Antibody Responses to Simian Virus 40 T Antigen: A Case-Control Study of Non-Hodgkin Lymphoma". Cancer Epidemiology, Biomarkers & Prevention. 14 (2): 521–4. doi:10.1158/1055-9965.epi-04-0441. PMID 15734981.
- Engels, Eric A.; Katki, Hormuzd A.; Nielsen, Nete M.; Winther, Jeanette F.; Hjalgrim, Henrik; Gjerris, Flemming; Rosenberg, Philip S.; Frisch, Morten (2003). "Cancer Incidence in Denmark Following Exposure to Poliovirus Vaccine Contaminated with Simian Virus 40". JNCI Journal of the National Cancer Institute. 95 (7): 532–9. CiteSeerX 10.1.1.500.5108. doi:10.1093/jnci/95.7.532. PMID 12671021.
- Institute of Medicine (US) Immunization Safety Review Committee; Stratton, K.; Almario, D. A.; McCormick, M. C. (2002). Stratton, Kathleen; Almario, Donna A.; McCormick, Marie C. (eds.). Immunization Safety Review: SV40 Contamination of Polio Vaccine and Cancer. The National Academy of Sciences. pp. 19–84. doi:10.17226/10534. ISBN 978-0-309-08610-3. PMID 25057632.
- Kroczynska, B; Cutrone, R; Bocchetta, M; Yang, H; Elmishad, A G; Vacek, P; Ramos-Nino, M; Mossman, BT; Pass, HI; Carbone, M (2006). "Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters". Proceedings of the National Academy of Sciences of the United States of America. 103 (38): 14128–33. Bibcode:2006PNAS..10314128K. doi:10.1073/pnas.0604544103. PMC 1599923. PMID 16966607.
- Pershouse, MA; Heivly, S; Girtsman, T (2006). "The role of SV40 in malignant mesothelioma and other human malignancies". Inhalation Toxicology. 18 (12): 995–1000. doi:10.1080/08958370600835377. PMID 16920674. S2CID 30590705.
- NIH/National Cancer Institute (25 August 2004). "Studies Find No Evidence That Simian Virus 40 Is Related To Human Cancer". Science Daily.
- Hilleman MR (1998). "Discovery of simian virus 40 (SV40) and its relationship to poliomyelitis virus vaccines". Dev Biol Stand. 94: 183–90. PMID 9776239.
- Carroll-Pankhurst, C; Engels, EA; Strickler, HD; Goedert, JJ; Wagner, J; Mortimer EA Jr. (November 2001). "Thirty-five year mortality following receipt of SV40- contaminated polio vaccine during the neonatal period". Br J Cancer. 85 (9): 1295–7. doi:10.1054/bjoc.2001.2065. PMC 2375249. PMID 11720463.
- Fanning, E; Zhao, K (2009). "SV40 DNA replication: from the A gene to a nanomachine". Virology. 384 (2): 352–359. doi:10.1016/j.virol.2008.11.038. PMC 2718763. PMID 19101707.
- Sowd, GA; Fanning, E (2012). "A wolf in sheep's clothing: SV40 co-opts host genome maintenance proteins to replicate viral DNA". PLOS Pathogens. 8 (11): e1002994. doi:10.1371/journal.ppat.1002994. PMC 3493471. PMID 23144614.
- Raghava, Smita; Giorda, Kristina M.; Romano, Fabian B.; Heuck, Alejandro P.; Hebert, Daniel N. (30 June 2011). "The SV40 Late Protein VP4 Is a Viroporin that Forms Pores to Disrupt Membranes for Viral Release". PLOS Pathogens. 7 (6): e1002116. doi:10.1371/journal.ppat.1002116. PMC 3128117. PMID 21738474.
- DeCaprio, James A.; Garcea, Robert L. (April 2013). "A cornucopia of human polyomaviruses". Nature Reviews Microbiology. 11 (4): 264–276. doi:10.1038/nrmicro2992. PMC 3928796. PMID 23474680.
- Henriksen, Stian; Rinaldo, Christine Hanssen (29 April 2020). "Does the Evidence Support the Existence of the Simian Polyomavirus SV40 Vp4 Viroporin?". mSphere. 5 (2): e00019-20. doi:10.1128/mSphere.00019-20. PMC 7082134. PMID 32188744.
- Daniels, Robert; Hebert, Daniel N. (29 April 2020). "In Support of Simian Polyomavirus 40 VP4 as a Later Expressed Viroporin". mSphere. 5 (2): e00187-20. doi:10.1128/mSphere.00187-20. PMC 7082142. PMID 32188752.
- Yamamoto, 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. PMID 4328814.
- Hall, 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. PMID 6294477. S2CID 5843939.
- Michod, Richard E.; Bernstein, Harris; Nedelcu, Aurora M. (2008). "Adaptive value of sex in microbial pathogens". Infection, Genetics and Evolution. 8 (3): 267–85. doi:10.1016/j.meegid.2008.01.002. PMID 18295550.
- Eibl, R. H.; Kleihues, P; Jat, P. S.; Wiestler, O. D. (1994). "A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen". The American Journal of Pathology. 144 (3): 556–64. PMC 1887088. PMID 8129041.
- 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. PMID 13774265. S2CID 38744505.
- 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. PMID 13889129.
- Reddy, V. B.; Weissman, S. M. (May 1978). "The genome of simian virus 40". Science. 200 (4341): 494–502. Bibcode:1978Sci...200..494R. doi:10.1126/science.205947. PMID 205947.
- Fiers, W; Contreras, R; Haegemann, G; Rogiers, R; Van De Voorde, A; Van Heuverswyn, H; Van Herreweghe, J; Volckaert, G; Ysebaert, M (May 1978). "Complete nucleotide sequence of SV40 DNA". Nature. 273 (5658): 113–20. Bibcode:1978Natur.273..113F. doi:10.1038/273113a0. PMID 205802. S2CID 1634424.
- Frequently Asked Questions about Cancer, Simian Virus 40 (SV40), and Polio Vaccine, Science Coordination and Innovation, United States Centers for Disease Control
NIH 1997 Conference on SV40
- Simian Virus 40 (SV40:) A Possible Human Polyomavirus Workshop Monday January 27, 1997, Morning Session, transcript of 1997 National Institutes of Health conference on SV40 in humans, (part 1 of 3), United States Food and Drug Administration (FDA)
- Simian Virus 40 (SV40:) A Possible Human Polyomavirus Workshop Monday January 27, 1997 Afternoon Session, transcript of 1997 National Institutes of Health conference on SV40 in humans (part 2 of 3), United States Food and Drug Administration (FDA)
- Simian Virus 40 (SV40:) A Possible Human Polyomavirus Workshop, Tuesday, 28 January 1997, transcript of 1997 National Institutes of Health conference on SV40 in humans (part 3 of 3 ), United States Food and Drug Administration (FDA)