SV40

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Simian virus 40
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Virus classification OOjs UI icon edit-ltr.svg
(unranked): Virus
Realm: Monodnaviria
Kingdom: Shotokuvirae
Phylum: Cossaviricota
Class: Papovaviricetes
Order: Sepolyvirales
Family: Polyomaviridae
Genus: Betapolyomavirus
Species:
Macaca mulatta polyomavirus 1
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 monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that is found to cause tumors in humans and 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 [1] and transcription. [2]

Contents

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. [3]

Human disease

The hypothesis that SV40 might 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. [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]

p53 damage and carcinogenicity

It has been suggested that SV40 may act as a co-carcinogen with crocidolite asbestos to cause mesothelioma. [7] [8]

Polio vaccine contamination

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]

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. [12] [13] [14]

Virology

SV40 consists of an unenveloped icosahedral virion with a closed circular double-stranded DNA genome [15] of 5.2 kb. [16] 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; [17] [18] however the presence and role of VP4 have been disputed. [19] [20]

Multiplicity reactivation

SV40 is capable of multiplicity reactivation (MR). [21] [22] 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. [21] Hall studied MR when SV 40 virions were exposed to the DNA crosslinking agent 4, 5', 8-trimethylpsoralen. [22] 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. [22] 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. [23]

Transcription

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.[ citation needed ]

Other 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 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. [24]

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 ]

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. [25] In 1962, Bernice Eddy described the SV40 oncogenic function inducing sarcoma and ependymomas in hamsters inoculated with monkeys cells infected with SV40. [26] The complete viral genome was sequenced by Weissman at Yale University (US) [27] in 1978 and also by Fiers and his team at the University of Ghent (Belgium). [28]

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. [3]

See also

Related Research Articles

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<i>Polyomaviridae</i> Family of viruses

Polyomaviridae is a family of viruses whose natural hosts are primarily mammals and birds. As of 2024, there are eight recognized genera. Fourteen species are known to infect humans, while others, such as Simian Virus 40, have been identified in humans to a lesser extent. Most of these viruses are very common and typically asymptomatic in most human populations studied. BK virus is associated with nephropathy in renal transplant and non-renal solid organ transplant patients, JC virus with progressive multifocal leukoencephalopathy, and Merkel cell virus with Merkel cell cancer.

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<span class="mw-page-title-main">SV40 large T antigen</span> Proto-oncogene derived from polyomavirus SV40

SV40 large T antigen is a hexamer protein that is a dominant-acting oncoprotein derived from the polyomavirus SV40. TAg is capable of inducing malignant transformation of a variety of cell types. The transforming activity of TAg is due in large part to its perturbation of the retinoblastoma (pRb) and p53 tumor suppressor proteins. In addition, TAg binds to several other cellular factors, including the transcriptional co-activators p300 and CBP, which may contribute to its transformation function. Similar proteins from related viruses are known as large tumor antigen in general.

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<span class="mw-page-title-main">Murine polyomavirus</span> Species of virus

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Janet S Butel is the Chairman and Distinguished Service Professor in the molecular virology and microbiology department at Baylor College of Medicine. Her area of expertise is on polyomavirus pathogenesis of infections and disease. She has more than 120 publications on PubMed. She also has 6 publications in Nature, which is considered one of the most prestigious science journals. She is a member of 9 different organizations and has 13 honors and awards.

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<span class="mw-page-title-main">Large tumor antigen</span>

The large tumor antigen is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. LTag is expressed early in the infectious cycle and is essential for viral proliferation. Containing four well-conserved protein domains as well as several intrinsically disordered regions, LTag is a fairly large multifunctional protein; in most polyomaviruses, it ranges from around 600-800 amino acids in length. LTag has two primary functions, both related to replication of the viral genome: it unwinds the virus's DNA to prepare it for replication, and it interacts with proteins in the host cell to dysregulate the cell cycle so that the host's DNA replication machinery can be used to replicate the virus's genome. Some polyomavirus LTag proteins - most notably the well-studied SV40 large tumor antigen from the SV40 virus - are oncoproteins that can induce neoplastic transformation in the host cell.

<span class="mw-page-title-main">Small tumor antigen</span>

The small tumor antigen is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. STag is expressed early in the infectious cycle and is usually not essential for viral proliferation, though in most polyomaviruses it does improve replication efficiency. The STag protein is expressed from a gene that overlaps the large tumor antigen (LTag) such that the two proteins share an N-terminal DnaJ-like domain but have distinct C-terminal regions. STag is known to interact with host cell proteins, most notably protein phosphatase 2A (PP2A), and may activate the expression of cellular proteins associated with the cell cycle transition to S phase. In some polyomaviruses - such as the well-studied SV40, which natively infects monkeys - STag is unable to induce neoplastic transformation in the host cell on its own, but its presence may increase the transforming efficiency of LTag. In other polyomaviruses, such as Merkel cell polyomavirus, which causes Merkel cell carcinoma in humans, STag appears to be important for replication and to be an oncoprotein in its own right.

The middle tumor antigen is a protein encoded in the genomes of some polyomaviruses, which are small double-stranded DNA viruses. MTag is expressed early in the infectious cycle along with two other related proteins, the small tumor antigen and large tumor antigen. MTag occurs only in a few known polyomaviruses, while STag and LTag are universal - it was first identified in mouse polyomavirus (MPyV), the first polyomavirus discovered, and also occurs in hamster polyomavirus. In MPyV, MTag is an efficient oncoprotein that can be sufficient to induce neoplastic transformation in some cells.

References

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  2. ↑ 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.
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  12. ↑ Mueller, C.; Strayer, M. S.; Sirninger, J.; Braag, S.; Branco, F.; Louboutin, J.-P.; Flotte, T. R.; Strayer, D. S. (February 2010). "In vitro and in vivo functional characterization of gutless recombinant SV40-derived CFTR vectors". Gene Therapy. 17 (2): 227–237. doi:10.1038/gt.2009.137. PMC   2820588 . PMID   19890354.
  13. ↑ Toscano, Miguel G.; van der Velden, Jeroen; van der Werf, Sybrand; Odijk, Machteld; Roque, Ana; Camacho-Garcia, Rafael J.; Herrera-Gomez, Irene G.; Mancini, Irene; de Haan, Peter (15 September 2017). "Generation of a Vero-Based Packaging Cell Line to Produce SV40 Gene Delivery Vectors for Use in Clinical Gene Therapy Studies". Molecular Therapy. Methods & Clinical Development. 6: 124–134. doi:10.1016/j.omtm.2017.06.007. PMC   5537168 . PMID   28791314.
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  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
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