Simian virus 40

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1. Classification

a. Higher order taxa

Kingdom: Viruses; Phylum: Cossaviricota; Class: Papovaviricetes; Order: Sepolyvirales; Family: Polyomaviridae [[#National Center for Biotechnology Information (NCBI)[Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information. Betapolyomavirus macacae. https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=1891767 |[1]]]

b. Species

Simian Virus 40, commonly known as SV40, is a virus that is a member of the Betapolyomavirus macacae taxonomic group.

2. Description and significance

Simian Virus 40 (SV40) is a small, double-stranded DNA virus that is becoming widely known for its role as an emergent human pathogen. The notoriety of the virus stems from the potential role in human cancer and its association with contaminated polio vaccines in the mid-20th century [2]. There was, and still is, controversy about if SV40 is a cancer-causing virus in humans, as many believe the oncogenic effects were limited to the monkey populations where the virus originated [2]. However, in recent years, scientists have found associations between SV40 and various human cancers, including colon cancer [3], mesotheliomas, which is an aggressive cancer typically found in the lungs and chest [4], and osteosarcomas, a certain type of bone cancer [5]. Furthermore, SV40 has been used as a vector for gene delivery and has the potential to treat many diseases (REFs) While there is extensive research on SV40, we still lack crucial information about SV40s mechanisms for initiating DNA replication and the oncogenic mechanisms that allow SV40 to cause cancers [6].

3. Genome structure

The genome of SV40 is a circular double stranded DNA molecule that has a molecular weight of about 3.0 x 106 Da [7]. It is approximately 5.25 kilobases in length with several different DNA sequences that can be recognized by restriction enzymes [8]. SV40 codes for two nonstructural viral proteins, the large tumor antigen and the small tumor antigen [9]. SV40’s DNA is split into a transcribable region and a regulatory region. The regulatory region contains SV40’s origin of replication and binding sites, which control gene expression and terminate expression using a polyadenylation signal [9]. SV40 can be used as a vector for other DNA sequences, and this can be generated by deleting parts of the coding region which opens up space in the genome [8]. The specific deletion sequences consist of the non-structural T-antigens. [8]

DNA mapping of SV40 was conducted using restriction enzymes that worked specifically for double stranded DNA [7]. Researchers found 15 cleavage site map points, with the furthest distance of 760 map units from the Eco-RI recognition site, which served as the origin point [7]. The Eco-RI site is a marker where the restriction enzyme Eco-R1 can cleave the DNA. The cleavage site map points gave researchers a better understanding of the SV40 genomic structure.

4. Cell structure

SV40 particles are small and spherical, with a diameter of approximately 45 nm, and the estimated weight of the whole particle is 270 kDa [10]. The virus is coated with proteins that allow it to attach and obtain entry into the host cells [11]. The protein coat consists of three major capsid proteins attached to the outside of the particle: VP1, VP2, and VP3, of which VP1 is the highest in percentage of the protein coating [10]. SV40 also has histones that help package its viral DNA [10]. The virus strictly replicates in the kidney cells of its natural host, non-human primates called macaques [12]. SV40 infects cells through pockets in the cell membrane and endosomes [8].

5. Metabolic processes

SV40 induces aerobic glycolysis in its host cells for its replication and survival [13]. SV40 modifies metabolism in order to support its rapid proliferation, called the Warburg effect, to ensure its growth, survival and overall long-term maintenance [14]. SV40 increases the rate of uptake of glucose and fermentation of glucose to lactate [15].

6. Ecology

SV40 has been found in the rhesus macaque (Macacca mulatta) as well as in other species of Asian macaque monkeys [16]. Other monkey species that have been infected include the African green monkey (Chlorocebus aethiops) and the crab-eating macaque (Macaca fascicularis). SV40 infections were mostly detected in the kidneys of monkeys, indicating that urine may have been the means of transmission in these animals [17]. SV40 DNA has also been found in the brain, spleen, and in peripheral blood mononuclear cells, a particular cell found in the blood of monkeys, suggesting SV40 may spread through its host’s blood [16]. While SV40 infections are often benign, they can become pathogenic if the host is immunocompromised, which is often the case in monkeys that are infected with a simian immunodeficiency virus. In those cases, SV40 is present in the brain, indicating the central nervous system may be affected [7]. Though it is most prevalent in monkeys, SV40 has also infected humans [2].

7. Pathology

After its discovery within the human population from contaminated vaccines, Simian Virus 40 has been studied for its possible associations with human disease [18]. The identification of SV40 in human urine has been connected to the loss of specialized cells and immune cells within the kidneys resulting in the possibility of kidney disease [18]. Other studies have shown that SV40 antigens play a possible role in the development of human osteosarcoma, with patients showing a higher chance of being infected with the virus [10]. Researchers discovered that SV40 can bind to the membrane of neighboring cells and induce signaling within the cell to begin rupturing its own cell membrane allowing the virus to be released [19]. By being released, SV40 is able to continue with this cycle and infect more cells that it comes in contact with [19].

8. Current Research

The distribution of SV40 in contaminated polio vaccines from 1955-1963 raised substantial concerns and sparked a surge of research into the virus [2]. Much of the research involving SV40 centers around its involvement in different types of cancer, including human osteosarcoma and colon cancer. SV40 is not present in healthy tissues but was detected in the tissue samples of colon cancer patients [3]. The results did not show a statistically significant association between the abundance of SV40 and disease state [3]. Since that study, more research has found that there is a statistically significant increase in the presence of SV40 Tag antibodies in patients with osteosarcoma when compared to healthy subjects and breast cancer patients (a cancer not associated with SV40) [20]. The specific impacts of SV40 in the progression of osteosarcoma and its treatment is still unknown.

SV40 is being used as a vector for gene delivery, with potential for gene therapy and the development of a new class of medicines [8]. SV40 vectors are known to be stable and well tolerated by the human’s immune system, and might be effective in treating genetic disorders, cancer, diabetes, as well as a range of other major diseases [8]. Studies have shown that recombinant SV40-derived vectors (rSV40s) can transduce human neurons effectively in vitro and in rodent brains in vivo and that they may be useful for long-term expression in monkey, and potentially human, brains [21]. SV40 large T antigen (SV40T) continues to be utilized to enhance gene expression [22]. Some concern has been raised about the potential impacts of residual DNA coding in SV40T which may inhibit p53 growth suppressive functions [22]. This study highlights the importance of expensive testing to ensure that methods, such as gene transfer vectors, will not result in unintended issues prior to utilizing them on research that can potentially impact human health.

9. References

[[#National Center for Biotechnology Information (NCBI)[Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information. Betapolyomavirus macacae. https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=1891767 |[1]]] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]