| Simian virus 40 | |
|---|---|
 | |
Virus classification | |
| (unranked): | Virus |
| Realm: | Monodnaviria |
| Kingdom: | Shotokuvirae |
| Phylum: | Cossaviricota |
| Class: | Papovaviricetes |
| Order: | Sepolyvirales |
| Family: | Polyomaviridae |
| Genus: | Betapolyomavirus |
| Species: | |
| Virus: | Simian virus 40 |
| Synonyms | |
simian vacuolating virus 40, SV40 | |
SV40 is an abbreviation forsimian vacuolating virus 40 orsimian virus 40, apolyomavirus that is found in bothmonkeys andhumans. Like other polyomaviruses, SV40 is aDNA virus that is found to causetumors in humans and animals, but most often persists as a latent infection. SV40 has been widely studied as amodel eukaryotic virus, leading to many early discoveries in eukaryoticDNA replication[1] andtranscription.[2]
Following contamination ofpolio 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 acause célèbre foranti-vaccination activists, who have blamed it for multiple ills, including cancer andHIV/AIDS.[3]
The hypothesis that SV40 mightcause 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]
It has been suggested that SV40 may act as aco-carcinogen withcrocidolite asbestos to causemesothelioma.[7][8]
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]
Due to its hightissue tropism,biotechnology companies seek to utilize modified SV40 based vectors as aviral vector forgene therapy. In thesehelper dependent virus or packaging cell line assisted produced vectors theSV40 large T antigen and SV40 small T antigen are removed.[12][13][14]
SV40 consists of anunenvelopedicosahedralvirion with a closed circular double-stranded DNA genome[15] of 5.2 kb.[16] 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.[17] Penetration into the cell is through acaveolinvesicle. 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 ofEndoplasmic-reticulum-associated protein degradation machinery to penetrate the ER membrane and get extracted into the cytosol.[18] A dynein motor complex adaptor,BICD2, disassembles the virion further,[19] before components of theLINC complex target the virion to the nuclear membrane for subsequent entry.[20] Inside thecell nucleus, the cellularRNA polymerase II acts to promote early gene expression. This results in anmRNA that is spliced into two segments. The small and large Tantigens result from this. The large T antigen has two functions: 5% goes to the plasmacell 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 earlyRNA synthesis. Binding to site II takes place in each cell cycle. Binding site I initiates DNA replication at theorigin of replication. Early transcription gives two spliced RNAs that are both 19s. Late transcription gives both a longer 16s, which synthesizes the major viralcapsid protein VP1; and the smaller 19s, which gives VP2 and VP3 throughleaky 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 aviroporin facilitiating release of viral particles and resulting incytolysis;[21][22] however the presence and role of VP4 have been disputed.[23][24]
SV40 is capable ofmultiplicity reactivation (MR).[25][26] 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 withUV light and allowed to undergo multiple infection of host cells.[25] Hall studied MR when SV 40 virions were exposed to the DNA crosslinking agent 4, 5', 8-trimethylpsoralen.[26] 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.[26] 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.[27]
The earlypromoter for SV40 contains three elements. TheTATA box is located approximately 20base-pairs upstream from thetranscriptional start site. The 21 base-pair repeats contain sixGC boxes and are the site that determines the direction of transcription. Also, the 72 base-pair repeats are transcriptionalenhancers. When theSP1 protein interacts with the 21 base-pair repeats, it binds either the first or the last three GC boxes. Binding the first three initiates earlyexpression, 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 theAP-1 transcription factor to give a primary transcript that is 3'polyadenylated and 5' capped.[citation needed]
SV40 is dormant and is asymptomatic inrhesus monkeys. The virus has been found in manymacaque populations in the wild, where it rarely causes disease. However, in monkeys that areimmunodeficient—due to, for example, infection withsimian immunodeficiency virus—SV40 acts much like the humanJC andBK polyomaviruses, producing kidney disease and sometimes ademyelinating disease similar toprogressive multifocal leukoencephalopathy. In other species, particularlyhamsters, SV40 causes a variety of tumors, generally sarcomas. In rats, the oncogenicSV40 large T antigen was used to establish a brain tumor model forprimitive neuroectodermal tumor andmedulloblastoma.[28]
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 was first identified by Ben Sweet andMaurice Hilleman in 1960 when they found that between 10 and 30% of polio vaccines in the US were contaminated with SV40.[29] In 1962,Bernice Eddy described the SV40oncogenic function inducingsarcoma andependymomas in hamsters inoculated with monkeys cells infected with SV40.[30] The complete viralgenome was sequenced byWeissman atYale University (US)[31] in 1978 and also byFiers and his team at theUniversity of Ghent (Belgium).[32]
SV40 has become a totemic subject amonganti-vaccination activists, where its presence in contaminated vaccine is accused of being a cause of a cancer "epidemic" and of being responsible forHIV/AIDS.[3]
