|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. Like other polyomaviruses, SV40 is a DNA virus that has the potential to cause tumors, but most often persists as a latent infection.
SV40 became a highly controversial subject after it was revealed that millions were exposed to the virus after receiving a contaminated polio vaccine produced between 1955 and 1961.
The virus was first identified by Bernice E. Eddy (based on a work of her and Sarah Stewart about Polyoma viruses) in 1960 in cultures of rhesus monkey kidney cells that were being used to produce polio vaccine. It was named for the effect it produced on infected green monkey cells, which developed an unusual number of vacuoles. This observation was repeated and confirmed by Hilleman and Sweet who were employed by Merck in their vaccine division. The complete viral genome was sequenced by Walter Fiers and his team at the University of Ghent (Belgium) in 1978. The virus 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.
SV40 consists of an unenveloped icosahedral virion with a closed circular dsDNA genome of 5kb. The virion adheres to cell surface receptors of MHC class 1 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% will go to the plasma membrane of the cell and 95% will return 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 in the nucleus. 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 where 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 of the first three initiates early expression and binding of 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.
Theorized role in human disease
The hypothesis that SV40 might cause cancer in humans has been a particularly controversial area of research. Several different methods have been used to detect 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. However, the United States 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 is based on two recent 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 and which were also likely to have infected Dr. Eddy's hamsters, can cause prostate cells to turn cancerous. Whether or not this is true for other human cells is debatable.
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 the 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 produced 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.
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, but no samples prior to 1962 could initially be found. Then, 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 being 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. Although horizontal transmission between people has been proposed, it is not clear if this actually happens and if it does, how frequently it occurs.
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.
- Le Page, Michael (2004-06-10). "Does SV40 contamination matter?". New Scientist. Retrieved 2010-03-29. "More than 40 years after SV40 was first discovered, in polio vaccine, these crucial questions remain fiercely controversial. (See work and death of researcher Mary Sherman.),"
- BE Eddy, GS Borman, WH Berkeley, and RD Young (1961). "Tumors induced in hamsters by injection of rhesus monkey kidney cell extracts". Proceedings of the Society for Experimental Biology and Medicine, 107(1):191–197. PMID 13725644.
- Fiers W et al., Complete nucleotide-sequence of SV40 DNA, Nature, 273, 113–120, 1978
- Eibl RH, Kleihues P, Jat PS, Wiestler OD (1994) A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen. Am J Pathol. 1994 Mar;144(3):556–64
- Yamamoto H, 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 JD (1982). "Repair of psoralen-induced crosslinks in cells multiply infected with SV40". Mol. Gen. Genet. 188 (1): 135–8. doi:10.1007/bf00333007. PMID 6294477.
- Michod RE, Bernstein H, Nedelcu AM (2008). Adaptive value of sex in microbial pathogens. Infect Genet Evol 8(3):267–285. PMID 18295550 http://www.hummingbirds.arizona.edu/Faculty/Michod/Downloads/IGE%20review%20sex.pdf
- Poulin DL, DeCaprio JA (2006). "Is there a role for SV40 in human cancer?". J. Clin. Oncol. 24 (26): 4356–65. doi:10.1200/JCO.2005.03.7101. PMID 16963733.
- Lowe DB, Shearer MH, Jumper CA, Kennedy RC (2007). "SV40 association with human malignancies and mechanisms of tumor immunity by large tumor antigen". Cell. Mol. Life Sci. 64 (7–8): 803–14. doi:10.1007/s00018-007-6414-6. PMID 17260087.
- Shah KV (2007). "SV40 and human cancer: a review of recent data". Int. J. 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". Cell. Mol. Life Sci. 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 website, Posted: 08/23/2004, Updated: 03/01/2005[dead link]
- Antibody Responses to Simian Virus 40 T Antigen: A Case-Control Study of Non-Hodgkin Lymphoma, Eric A. Engels, Jinbo Chen, Patricia Hartge, James R. Cerhan, Scott Davis, Richard K. Severson, Wendy Cozen and Raphael P. Viscidi, Cancer Epidemiology Biomarkers & Prevention Vol. 14, 521–524, February 2005
- Cancer Incidence in Denmark Following Exposure to Poliovirus Vaccine Contaminated With Simian Virus 40, Eric A. Engels, Hormuzd A. Katki, Nete M. Nielsen, Jeanette F. Winther, Henrik Hjalgrim, Flemming Gjerris, Philip S. Rosenberg, Morten Frisch, Journal of the National Cancer Institute, Vol. 95, No. 7, 532–539, 2 April 2003
- "The National Academy of Sciences“Immunization Safety Review: SV40 Contamination of Polio Vaccine and Cancer (2002)" by Kathleen Stratton, Donna A. Almario, and Marie C. McCormick, Editors, Immunization Safety Review Committee.
- "Persistant exposure to Mycoplasma Induces Malignant Transformation of Human Prostate Cells", Kazunori Namiki, Steve Goodison, Stacy Porvasnik, Robert W. Allan, Kenneth A. Iczkowski, Cydney Urbanek, Leticia Reyes, Noboru Sakamoto, and Charles J. Rosser,PLoS One. 2009; 4(9): e6872., Published online 2009 September 1. doi: 10.1371/journal.pone.0006872, PMCID: PMC2730529
- Kroczynska, B; Cutrone R; Bocchetta M; Yang H; Elmishad A; Vacek P; Ramos-Nino M; Mossman B; Pass H; Carbone M (2006). "Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters". PNAS 103 (38): 14128–33. doi:10.1073/pnas.0604544103. PMC 1599923. PMID 16966607.
- Pershouse M, Heivly S, Girtsman T (2006). "The role of SV40 in malignant mesothelioma and other human malignancies". Inhal Toxicol 18 (12): 995–1000. doi:10.1080/08958370600835377. PMID 16920674.
- 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.
- Nature, the Physician, and the Family: Selected Writings of Herbert Ratner, M.D., Mary Tim Baggott, M.D., editor, AuthorHouse, 2007, ISBN 978-1-4184-7510-9, xv–xvii.
- The Virus and the Vaccine, Debbie Bookchin and Jim Schumacher, St. Martin's Press, 2004, ISBN 0-312-27872-1, 226–28.
- Rizzo P, Di Resta I, Powers A, Ratner H, and Carbone M. Unique strains of SV40 in commercial poliovaccines from 1955 not readily Identifiable with current testing for SV40 infection. Cancer Res1999 (59):6103–8.
- Martini F, Corallini A, Balatti V, Sabbioni S, Pancaldi C, Tognon M (2007). "Simian virus 40 in humans". Infect. Agents Cancer 2: 13. doi:10.1186/1750-9378-2-13. PMC 1941725. PMID 17620119.
- Vaccine scandal revives cancer fear, Debbie Bookchin, New Scientist, 7 July 2004
- 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)
- Simian virus 40 at the US National Library of Medicine Medical Subject Headings (MeSH)
- SV40 entry in the NCBI Taxonomy database
- SV40 entry in the NCBI Genome database