View source for SV40

{{Short description|Species of virus}}
{{Use dmy dates|date=April 2022}}
{{Virusbox
| image = Symian virus.png
| parent = Betapolyomavirus
| species = Betapolyomavirus macacae
| virus = Simian virus 40
| synonyms = simian vacuolating virus 40, SV40
}}
'''SV40''' is an abbreviation for '''simian vacuolating virus 40''' or '''simian virus 40''', a [[polyomavirus]] that is found in both [[monkey]]s and [[human]]s. Like other polyomaviruses, SV40 is a [[DNA virus]] that is found to cause [[tumor]]s in humans and animals, but most often persists as a dormant infection. SV40 has been widely studied as a [[Model organism|model]] eukaryotic virus, leading to many early discoveries in eukaryotic [[DNA replication]]<ref>{{Cite journal |volume=384 |issue=2 |pages=352–359 |date=February 2009 |pmid=19101707 |pmc=2718763 |last1=Fanning |first1=E |last2=Zhao |first2=K |title=SV40 DNA replication: From the A gene to a nanomachine |journal=Virology |doi=10.1016/j.virol.2008.11.038 }}</ref> and [[Transcription (biology)|transcription]].<ref>{{cite journal|last1=Banerji|first1=J|last2=Rusconi|first2=S|last3=Schaffner|first3=W|title=Expression of a β-globin gene is enhanced by remote SV40 DNA sequences|journal=Cell|date=December 1981|volume=27|issue=2|pages=299–308|pmid=6277502|doi=10.1016/0092-8674(81)90413-X|s2cid=54234674}}</ref>

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]].<ref name=sbm/>

==Human disease==
The hypothesis that SV40 might [[Oncovirus|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.<ref>{{cite journal |doi=10.1200/JCO.2005.03.7101|pmid=16963733|title=Is There a Role for SV40 in Human Cancer?|journal=Journal of Clinical Oncology|volume=24|issue=26|pages=4356–65|year=2006|last1=Poulin|first1=D. L.|last2=Decaprio|first2=J. A.}}</ref> "Persuasive evidence now indicates that SV40 is causing infections in humans today and represents an emerging pathogen."<ref>{{Cite journal |last1=Vilchez |first1=Regis A. |last2=Butel |first2=Janet S. |date=July 2004 |title=Emergent Human Pathogen Simian Virus 40 and Its Role in Cancer |journal=Clinical Microbiology Reviews |language=en |volume=17 |issue=3 |pages=495–508 |doi=10.1128/CMR.17.3.495-508.2004 |pmid=15258090 |s2cid=10372679 |issn=0893-8512|doi-access=free |pmc=452549 }}</ref> However "It appears unlikely that SV40 infection alone is sufficient to cause human malignancy..."<ref>{{cite journal |vauthors=Qi F, Carbone M, Yang H, Gaudino G |title=Simian virus 40 transformation, malignant mesothelioma and brain tumors |journal=Expert Rev Respir Med |volume=5 |issue=5 |pages=683–97 |date=October 2011 |pmid=21955238 |pmc=3241931 |doi=10.1586/ers.11.51 |type=Review}}</ref>

===p53 damage and carcinogenicity===
It has been suggested that SV40 may act as a [[co-carcinogen]] with [[Riebeckite#Crocidolite (fibrous riebeckite)|crocidolite asbestos]] to cause [[mesothelioma]].<ref>{{cite journal |last1=Kroczynska |first1=Barbara |last2=Cutrone |first2=Rochelle |last3=Bocchetta |first3=Maurizio |last4=Yang |first4=Haining |last5=Elmishad |first5=Amira G. |last6=Vacek |first6=Pamela |last7=Ramos-Nino |first7=Maria |last8=Mossman |first8=Brooke T. |last9=Pass |first9=Harvey I. |last10=Carbone |first10=Michele |title=Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters |journal=Proceedings of the National Academy of Sciences |date=19 September 2006 |volume=103 |issue=38 |pages=14128–14133 |doi=10.1073/pnas.0604544103 |pmid=16966607 |pmc=1599923 |bibcode=2006PNAS..10314128K |doi-access=free }}</ref><ref>{{cite journal |last1=Pershouse |first1=Mark A. |last2=Heivly |first2=Shane |last3=Girtsman |first3=Teri |title=The Role of SV40 in Malignant Mesothelioma and Other Human Malignancies |journal=Inhalation Toxicology |date=January 2006 |volume=18 |issue=12 |pages=995–1000 |doi=10.1080/08958370600835377 |pmid=16920674 |bibcode=2006InhTx..18..995P |s2cid=30590705 }}</ref>

===Polio vaccine contamination===

{{Main|Vaccine contamination with SV40}}
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,<ref name="ScienceDaily">{{cite press release |url=https://www.sciencedaily.com/releases/2004/08/040825092736.htm |title=Studies Find No Evidence That Simian Virus 40 Is Related To Human Cancer |publisher=NIH/National Cancer Institute |website=Science Daily |date=25 August 2004 }}</ref> though SV40 has been extensively studied.<ref name="DevBiolStand">{{cite journal | title=Discovery of simian virus 40 (SV40) and its relationship to poliomyelitis virus vaccines. | author=Hilleman MR | journal=Dev Biol Stand | year=1998 | volume=94 | pages=183–90 | pmid=9776239}}</ref> A thirty-five year follow-up did not find excess numbers of cancers associated with SV40.<ref name="BJCancer35">{{cite journal | title=Thirty-five year mortality following receipt of SV40- contaminated polio vaccine during the neonatal period. |author1=Carroll-Pankhurst, C |author2=Engels, EA |author3=Strickler, HD |author4=Goedert, JJ |author5=Wagner, J |author6=Mortimer EA Jr. | journal=Br J Cancer |date=Nov 2001  | volume=85 | issue=9 | pages=1295–7 | pmid=11720463 | doi=10.1054/bjoc.2001.2065 | pmc=2375249}}</ref>

==Gene therapy==
Due to its high [[tissue tropism]], [[biotechnology]] companies seek to utilize modified SV40 based vectors as a [[viral vector]] for [[gene therapy]]. In these [[helper dependent virus]] or packaging cell line assisted produced vectors the [[SV40 large T antigen]] and SV40 small T antigen are removed.<ref>{{cite journal |last1=Mueller |first1=C. |last2=Strayer |first2=M. S. |last3=Sirninger |first3=J. |last4=Braag |first4=S. |last5=Branco |first5=F. |last6=Louboutin |first6=J.-P. |last7=Flotte |first7=T. R. |last8=Strayer |first8=D. S. |title=In vitro and in vivo functional characterization of gutless recombinant SV40-derived CFTR vectors |journal=Gene Therapy |date=February 2010 |volume=17 |issue=2 |pages=227–237 |doi=10.1038/gt.2009.137 |pmid=19890354 |pmc=2820588 }}</ref><ref>{{cite journal |last1=Toscano |first1=Miguel G. |last2=van der Velden |first2=Jeroen |last3=van der Werf |first3=Sybrand |last4=Odijk |first4=Machteld |last5=Roque |first5=Ana |last6=Camacho-Garcia |first6=Rafael J. |last7=Herrera-Gomez |first7=Irene G. |last8=Mancini |first8=Irene |last9=de Haan |first9=Peter |title=Generation of a Vero-Based Packaging Cell Line to Produce SV40 Gene Delivery Vectors for Use in Clinical Gene Therapy Studies |journal=Molecular Therapy. Methods & Clinical Development |date=15 September 2017 |volume=6 |pages=124–134 |doi=10.1016/j.omtm.2017.06.007 |pmid=28791314 |pmc=5537168 }}</ref><ref>{{cite journal |last1=Vera |first1=Maria |last2=Fortes |first2=Puri |title=Simian Virus-40 as a Gene Therapy Vector |journal=DNA and Cell Biology |date=May 2004 |volume=23 |issue=5 |pages=271–282 |doi=10.1089/104454904323090903 |pmid=15169607 }}</ref>

==Virology==

SV40 consists of an [[Viral envelope|unenveloped]] [[Regular icosahedron|icosahedral]] [[Virus|virion]] with a closed circular double-stranded DNA genome<ref>{{cite journal | volume=384 | issue=2 | pages=352–359 | year=2009 | doi=10.1016/j.virol.2008.11.038 | pmid=19101707 | pmc=2718763 | last1=Fanning | first1=E | last2=Zhao | first2=K | title=SV40 DNA replication: from the A gene to a nanomachine | journal=Virology }}</ref> of 5.2 kb.<ref>{{cite journal | volume=8 | issue=11 | article-number=e1002994 | year=2012 | doi=10.1371/journal.ppat.1002994 | pmid=23144614 | pmc=3493471 | last1=Sowd | first1=GA | last2=Fanning | first2=E | title=A wolf in sheep's clothing: SV40 co-opts host genome maintenance proteins to replicate viral DNA | journal=PLOS Pathogens | doi-access=free }}</ref> Structurally, SV40 is composed of 72 pentamers of major capsid protein VP1, with each VP1 pentamers harboring one minor capsid protein, either VP2 or VP3. The virion undergoes receptor-mediated endocytosis after binding to the ganglioside GM1 on the cell membrane.<ref>{{cite journal |pmid=12941687 |date=2003 |last1=Tsai |first1=B. |last2=Gilbert |first2=J. M. |last3=Stehle |first3=T. |last4=Lencer |first4=W. |last5=Benjamin |first5=T. L. |last6=Rapoport |first6=T. A. |title=Gangliosides are receptors for murine polyoma virus and SV40 |journal=The EMBO Journal |volume=22 |issue=17 |pages=4346–4355 |doi=10.1093/emboj/cdg439 |pmc=202381 }}</ref> Penetration into the cell is through a [[caveolin]] [[Vesicle (biology and chemistry)|vesicle]]. The endosome carrying SV40 fuses with the ER membrane to deliver the virus into the lumen of the ER. Resident ER proteins induce structural changes to initiate a disassembly process of the VP1 capsid shell. SV40 then exploits components of [[Endoplasmic-reticulum-associated protein degradation]] machinery to penetrate the ER membrane and get extracted into the cytosol.<ref>{{cite journal |pmid=21589906 |date=2011 |last1=Inoue |first1=T. |last2=Tsai |first2=B. |title=A large and intact viral particle penetrates the endoplasmic reticulum membrane to reach the cytosol |journal=PLOS Pathogens |volume=7 |issue=5 |article-number=e1002037 |doi=10.1371/journal.ppat.1002037 |doi-access=free |pmc=3093372 }}</ref> A dynein motor complex adaptor, [[BICD2]], disassembles the virion further,<ref>{{cite journal |pmid=32259203 |date=2020 |last1=Spriggs |first1=C. C. |last2=Badieyan |first2=S. |last3=Verhey |first3=K. J. |last4=Cianfrocco |first4=M. A. |last5=Tsai |first5=B. |title=Golgi-associated BICD adaptors couple ER membrane penetration and disassembly of a viral cargo |journal=The Journal of Cell Biology |volume=219 |issue=5 |doi=10.1083/jcb.201908099 |pmc=7199864 }}</ref> before components of the [[LINC complex]] target the virion to the nuclear membrane for subsequent entry.<ref>{{cite journal |pmid=36067270 |date=2022 |last1=Spriggs |first1=C. C. |last2=Cha |first2=G. |last3=Li |first3=J. |last4=Tsai |first4=B. |title=Components of the LINC and NPC complexes coordinately target and translocate a virus into the nucleus to promote infection |journal=PLOS Pathogens |volume=18 |issue=9 |article-number=e1010824 |doi=10.1371/journal.ppat.1010824 |doi-access=free |pmc=9481172 }}</ref> Inside the [[cell nucleus]], the cellular [[RNA polymerase II]] acts to promote early gene expression. This results in an [[Messenger RNA|mRNA]] that is spliced into two segments. The small and large T [[antigen]]s result from this. The large T antigen has two functions: 5% goes to the plasma [[Active transport|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 [[Transcription (genetics)|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]];<ref name="raghava_2011">{{cite journal |last1=Raghava |first1=Smita |last2=Giorda |first2=Kristina M. |last3=Romano |first3=Fabian B. |last4=Heuck |first4=Alejandro P. |last5=Hebert |first5=Daniel N. |title=The SV40 Late Protein VP4 Is a Viroporin that Forms Pores to Disrupt Membranes for Viral Release |journal=PLOS Pathogens |date=2011-06-30 |volume=7 |issue=6 |article-number=e1002116 |doi=10.1371/journal.ppat.1002116|pmid=21738474 |pmc=3128117 |doi-access=free }}</ref><ref name="decaprio_2013">{{cite journal |last1=DeCaprio |first1=James A. |last2=Garcea |first2=Robert L. |title=A cornucopia of human polyomaviruses |journal=Nature Reviews Microbiology |date=April 2013 |volume=11 |issue=4 |pages=264–276 |doi=10.1038/nrmicro2992|pmid=23474680 |pmc=3928796 }}</ref> however the presence and role of VP4 have been disputed.<ref name="henriksen_2020">{{cite journal |last1=Henriksen |first1=Stian |last2=Rinaldo |first2=Christine Hanssen |title=Does the Evidence Support the Existence of the Simian Polyomavirus SV40 Vp4 Viroporin? |journal=mSphere |date=2020-04-29 |volume=5 |issue=2 |article-number=e00019-20 |doi=10.1128/mSphere.00019-20|pmid=32188744 |pmc=7082134 }}</ref><ref name="daniels_2020">{{cite journal |last1=Daniels |first1=Robert |last2=Hebert |first2=Daniel N. |title=In Support of Simian Polyomavirus 40 VP4 as a Later Expressed Viroporin |journal=mSphere |date=2020-04-29 |volume=5 |issue=2 |article-number=e00187-20 |doi=10.1128/mSphere.00187-20|pmid=32188752 |pmc=7082142 }}</ref>

==Multiplicity reactivation==
SV40 is capable of [[multiplicity reactivation]] (MR).<ref name=Yamamoto>{{cite journal |last1=Yamamoto |first1=Hiroshi |last2=Shimojo |first2=H |date=August 1971 |title=Multiplicity reactivation of human adenovirus type 12 and simian virus 40 irradiated by ultraviolet light |journal=Virology |volume=45 |issue=2 |pages=529–31 |pmid=4328814 |doi= 10.1016/0042-6822(71)90355-2}}</ref><ref name=Hall>{{cite journal |volume=188 |issue=1 |pages=135–8 |year=1982 |pmid=6294477 |doi=10.1007/bf00333007 |last1=Hall |first1=J. D. |title=Repair of psoralen-induced crosslinks in cells multiply infected with SV40 |journal=Molecular & General Genetics|s2cid=5843939 }}</ref> MR is the process by which two or more virus genomes, each 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 [[Ultraviolet|UV light]] and allowed to undergo multiple infection of host cells.<ref name=Yamamoto /> Hall studied MR when SV 40 virions were exposed to the DNA crosslinking agent 4, 5', 8-trimethylpsoralen.<ref name=Hall /> 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.<ref name=Hall /> 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.<ref>{{cite journal |last1=Michod |first1=Richard E. |last2=Bernstein |first2=Harris |last3=Nedelcu |first3=Aurora M. |year=2008 |title=Adaptive value of sex in microbial pathogens |journal=Infection, Genetics and Evolution |volume=8 |issue=3 |pages=267–85 |doi=10.1016/j.meegid.2008.01.002 |pmid=18295550|bibcode=2008InfGE...8..267M }}</ref>

==Transcription==
The early [[Promoter (genetics)|promoter]] for SV40 contains three elements. The [[TATA box]] is located approximately 20 [[Base pair|base-pairs]] upstream from the [[Transcription (biology)|transcriptional]] start site. The 21 base-pair repeats contain six [[GC box]]es and are the site that determines the direction of transcription. Also, the 72 base-pair repeats are transcriptional [[Enhancer (genetics)|enhancers]]. When the [[Sp1 transcription factor|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 [[Gene expression|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 ([[Dimer (chemistry)|dimerization]]) with the [[AP-1 transcription factor]] to give a primary transcript that is 3' [[Polyadenylation|polyadenylated]] and 5' capped.{{citation needed|date=February 2015}}

==Other animals==
SV40 is dormant and is asymptomatic in [[rhesus macaque|rhesus monkeys]]. The virus has been found in many [[macaque]] populations in the wild, where it rarely causes disease. However, in monkeys that are [[immunodeficiency|immunodeficient]]—due to, for example, infection with ''[[simian immunodeficiency virus]]''—SV40 acts much like the human [[JC virus|JC]] and [[BK virus|BK]] polyomaviruses, producing kidney disease and sometimes a [[demyelinating disease]] similar to [[progressive multifocal leukoencephalopathy]]. In other species, particularly [[hamster]]s, 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]].<ref>{{cite journal |pmid=8129041|pmc=1887088|year=1994 |last1=Eibl|first1=R. H.|title=A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen|journal=The American Journal of Pathology|volume=144|issue=3|pages=556–64|last2=Kleihues|first2=P|last3=Jat|first3=P. S.|last4=Wiestler|first4=O. D.}}</ref>

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|date=February 2015}}

==History==
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 US were contaminated with SV40.<ref>{{Cite journal |volume=105 |issue=2 |pages=420–427 |date=November 1960 |pmid=13774265 |last1=Sweet |first1=B. H. |title=The vacuolating virus, S.V. 40 |journal=Proceedings of the Society for Experimental Biology and Medicine |last2=Hilleman |first2=M. R. |doi=10.3181/00379727-105-26128|s2cid=38744505 }}</ref> In 1962, [[Bernice Eddy]] described the SV40 [[Oncovirus|oncogenic]] function inducing [[sarcoma]] and [[ependymoma]]s in hamsters inoculated with monkeys cells infected with SV40.<ref>{{Cite journal |title=Identification of the oncogenic substance in rhesus monkey kidney cell culture as simian virus 40 |journal=Virology |volume=17 |pages=65–75 |date=May 1962 |pmid=13889129 |doi=10.1016/0042-6822(62)90082-x |last1=Eddy |first1=B. E. |last2=Borman |first2=G. S. |last3=Grubbs |first3=G. E. |last4=Young |first4=R. D. }}</ref> The complete viral [[genome]] was sequenced by [[Sherman Weissman|Weissman]] at [[Yale University]] (US)<ref>{{Cite journal |volume=200 |issue=4341 |pages=494–502 |date=May 1978 |pmid=205947 |last1=Reddy |first1=V. B. |title=The genome of simian virus 40 |journal=Science |last2=Weissman |first2=S. M. |doi=10.1126/science.205947|bibcode=1978Sci...200..494R }}</ref> in 1978 and also by [[Walter Fiers|Fiers]] and his team at the [[University of Ghent]] ([[Belgium]]).<ref>{{Cite journal |title=Complete nucleotide sequence of SV40 DNA |journal=Nature |volume=273 |issue=5658 |pages=113–20 |date=May 1978 |pmid=205802 |doi=10.1038/273113a0 |last1=Fiers |first1=W |last2=Contreras |first2=R |last3=Haegemann |first3=G |last4=Rogiers |first4=R |last5=Van De Voorde |first5=A |last6=Van Heuverswyn |first6=H |last7=Van Herreweghe |first7=J |last8=Volckaert |first8=G |last9=Ysebaert |first9=M  |bibcode=1978Natur.273..113F |s2cid=1634424 }}</ref>

== Culture and society ==
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]].<ref name=sbm>{{cite web |publisher=[[Science-Based Medicine]] |title=Another antivaccine zombie meme: polio vaccine and SV40 and cancer, oh, my! |author=Gorski DH|author-link=David Gorski |url=https://sciencebasedmedicine.org/another-antivaccine-zombie-meme-sv40-and-cancer-and-polio-oh-my/ |date=9 September 2013}}</ref>

==See also==
{{Portal|Viruses}}
* [[Mason-Pfizer monkey virus packaging signal]]
* [[SV40 Cancer Foundation]]

==References==
{{Reflist}}

== External links ==
{{Commons category}}

===CDC FAQ===
* "Simian Virus 40 (SV40) - 1955 – 1963" in {{cite web |title=Historical Safety Concerns |url=https://www.cdc.gov/vaccinesafety/concerns/concerns-history.html |website=Vaccine Safety |date=30 March 2022 |publisher=CDC }}

===Other===
* {{MeshName|Simian+virus+40}}
* [https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=10633 SV40] entry in the [https://web.archive.org/web/20081026005410/http://www.ncbi.nlm.nih.gov/sites/entrez?db=Taxonomy NCBI Taxonomy database]
* [https://www.ncbi.nlm.nih.gov/datasets/genome/?taxon=1891767 SV40] entry in the [https://web.archive.org/web/20021229193132/http://www.ncbi.nlm.nih.gov/genome/ NCBI Genome database]

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[[Category:Model organisms]]
[[Category:History of biotechnology]]
[[Category:Infraspecific virus taxa]]
[[Category:Polio]]
[[Category:Polyomaviridae]]