|Simian virus 40|
|Group:||Group I (dsDNA)|
|Species:||Simian virus 40|
|Classification and external resources|
SV40 is an abbreviation for Simian vacuolating virus 40 or Simian virus 40, a polyomavirus that is found in both monkeys and humans. It was named for the effect it produced on infected green monkey cells, which developed an unusual number of vacuoles. 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 was first identified by Ben Sweet and Maurice Hilleman in 1960 when they found that between 10-30% 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 Fiers and his team at the University of Ghent (Belgium) in 1978.
SV40 consists of an unenveloped icosahedral virion with a closed circular dsDNA 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. Eventual release of the viral particles is cytolytic and results in cell death.
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 bp repeats it binds either the first or the last three GC boxes. Binding the first three initiates early expression and binding the last three initiates late expression. The function of the 72 bp repeats is to enhance the amount of stable RNA and increase the rate of synthesis. This is done by binding (dimerization) with the AP1 (activator protein 1) to give a primary transcript that is 3' polyadenylated and 5' capped.
SV40 in animals
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 PML. 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 PNETs and medulloblastomas.
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.
Hypothesized role in human disease
The hypothesis that SV40 might cause cancer in humans has been a particularly controversial area of research. Several methods have detected SV40 in a variety of human cancers, although how reliable these detection methods are, and whether SV40 has any role in causing these tumors, remains unclear. 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.” However, Namika, Goodison,...and Rosser found that the SV40 large t-antigen, in combination with mycoplasma, often a contaminate of vaccines, can cause prostate cells to turn cancerous. Whether or not this is true for other human cells is debated.
p53 damage and carcinogenicity
SV40 is believed to suppress the transcriptional properties of the tumor-suppressing p53 in humans through the SV40 large T-antigen and SV40 small T-antigen. 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.
When SV40 infects nonpermissive cells, such as 3T3 mouse cells, the dsDNA of SV40 becomes covalently integrated. In nonpermissive cells only early gene expression occurs and this leads to transformation, or oncogenesis. The nonpermissive host needs the large T-antigen and the small t-antigen in order to function. The small T-antigen interacts with and integrates with the cellular phosphatase pp2A. This causes the cell to lose the ability to initiate transcription.
Polio vaccine contamination
Soon after its discovery, SV40 was identified in the oral form of the polio vaccine produced between 1955 and 1961 by American Home Products (dba Lederle). This is believed to be due to two sources: 1) SV40 contamination of the original seed strain (coded SOM); 2) contamination of the substrate—primary kidney cells from infected monkeys used to grow the vaccine virus during production. Both the Sabin vaccine (oral, live virus) and the Salk vaccine (injectable, killed virus) were affected; the technique used to inactivate the polio virus in the Salk vaccine, by means of formaldehyde, did not reliably kill SV40. The contaminated vaccine continued to be distributed to the public through 1963.
It was difficult to detect small quantities of virus until the advent of PCR; since then, stored samples of vaccine made after 1962 have tested negative for SV40. In 1997, Herbert Ratner of Oak Park, Illinois, gave some vials of 1954 Salk vaccine to researcher Michele Carbone. Ratner, the Health Commissioner of Oak Park at the time the Salk vaccine was introduced, had kept these vials of vaccine in a refrigerator for over forty years. Upon testing this vaccine, Carbone discovered that it contained not only the SV40 strain already known to have been in the Salk vaccine (containing two 72-bp enhancers) but also the same slow-growing SV40 strain currently found in some malignant tumors and lymphomas (containing one 72-bp enhancers). It is unknown how widespread the virus was among humans before the 1950s, though one study found that 12% of a sample of German medical students in 1952 had SV40 antibodies.
An analysis presented at the Vaccine Cell Substrate Conference in 2004 suggested that vaccines used in the former Soviet bloc countries, China, Japan, and Africa, could have been contaminated up to 1980, meaning that hundreds of millions more could have been exposed to the virus unknowingly.
Population level studies show no evidence of any increase in cancer incidence as a result of exposure, though SV40 has been extensively studied. A thirty-five year followup found no excess of the cancers putatively associated with SV40.
- Shah, K; Nathanson, N (January 1976). "Human exposure to SV40: Review and comment". American Journal of Epidemiology. 103 (1): 1–12. PMID 174424.
- Sweet, B. H.; Hilleman, M. R. (November 1960). "The vacuolating virus, S.V. 40". Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine. 105 (2): 420–427. doi:10.3181/00379727-105-26128. PMID 13774265.
- 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.
- 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.
- 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 . 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 . PMID 23144614.
- 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.
- 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 . PMID 8129041.
- 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.
- Shah, K. V. (2007). "SV40 and human cancer: A review of recent data". International Journal of Cancer. Journal International Du Cancer. 120 (2): 215–23. doi:10.1002/ijc.22425. PMID 17131333.
- Moens, U; Van Ghelue, M; Johannessen, M (2007). "Oncogenic potentials of the human polyomavirus regulatory proteins". Cellular and molecular life sciences : CMLS. 64 (13): 1656–78. doi:10.1007/s00018-007-7020-3. PMID 17483871.
- 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.
- 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. doi:10.1093/jnci/95.7.532. PMID 12671021.
- Stratton, Kathleen; Almario, Donna A.; McCormick, Marie C., eds. (2002). "Immunization Safety Review: SV40 Contamination of Polio Vaccine and Cancer". Immunization Safety Review: SV40 Contamination of Polio Vaccine and Cancer. The National Academy of Sciences. pp. 19–84. ISBN 978-0-309-08610-3.
- Namiki, K; Goodison, S; Porvasnik, S; Allan, R. W.; Iczkowski, K. A.; Urbanek, C; Reyes, L; Sakamoto, N; Rosser, C. J. (1 September 2009). "Persistent exposure to Mycoplasma induces malignant transformation of human prostate cells". PLoS ONE. 4 (9): e6872. Bibcode:2009PLoSO...4.6872N. doi:10.1371/journal.pone.0006872. PMC . PMID 19721714.
- Kroczynska, B; Cutrone, R; Bocchetta, M; Yang, H; Elmishad, A. G.; Vacek, P; Ramos-Nino, M; Mossman, B. T.; Pass, H. I.; 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 . PMID 16966607.
- Pershouse, M. A.; 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.
- CDC website http://www.cdc.gov/vaccinesafety/concerns/concerns-history.html Accessed Nov 1, 2016
- Study Is Unsure on Tainted Polio Vaccine's Cancer Role. Denise Grady. NY Times. Oct 23, 2002 http://www.nytimes.com/2002/10/23/us/study-is-unsure-on-tainted-polio-vaccine-s-cancer-role.html Accessed Nov 1, 2016
- Ferber, Dan (2002). "Virology. Monkey virus link to cancer grows stronger". Science. 296 (5570): 1012–1015. doi:10.1126/science.296.5570.1012. PMID 12004103. Archived from the original on May 10, 2002.
- Baggott, Mary Tim, ed. (2007). Nature, the Physician, and the Family: Selected Writings of Herbert Ratner, M.D. AuthorHouse. pp. xv–xvii. ISBN 978-1-4184-7510-9.[self-published source?]
- Bookchin, Debbie; Schumacher, Jim (2004). The Virus and the Vaccine. St. Martin's Press. pp. 226–28. ISBN 0-312-27872-1.
- Rizzo, Paola; Di Resta, Ilaria; Powers, Amy; Ratner, Herbert; Carbone, Michele (1999). "Unique Strains of SV40 in Commercial Poliovaccines from 1955 Not Readily Identifiable with Current Testing for SV40 Infection". Cancer Research. 59 (24): 6103–8. PMID 10626798.
- Martini, F; Corallini, A; Balatti, V; Sabbioni, S; Pancaldi, C; Tognon, M (9 July 2007). "Simian virus 40 in humans". Infectious agents and cancer. 2: 13. doi:10.1186/1750-9378-2-13. PMC . PMID 17620119.
- Bookchin, Debbie (7 July 2004). "Vaccine scandal revives cancer fear". New Scientist.
- NIH/National Cancer Institute (2004-08-25). "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. (Nov 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. PMID 11720463.
- 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)