Cartoon Image of SV40
http://www.cgl.ucsf.edu/Research/virus/capsids/1sva-5A-large.jpg
By Jon Wong and Caroline Pletcher
Cartoon Image of SV40
http://www.cgl.ucsf.edu/Research/virus/capsids/1sva-5A-large.jpg
Polyomavirus Essential Information
New Polyoma Findings from 2004-2005
Helpful Polyomavirus Links
Pathogen Cards
References
The virus family polyomaviridae, along with papillomaviridae, was once a subfamily of papovavirdae. Papovaviridae was derived from papillomavirus (pa-), polyvirus (-po-), and simian vacuolating virus (-va). A double stranded DNA virus, polyomaviruses are known to cause tumors, though not in humans. Appropriately, the name polyoma means “many tumors”. Other important characteristics of polyomaviruses are that they have a genome of approximately 5 kilobases, a virion of about 45 nm in diameter, cellular histones that form a supercoiled minichromosome, naked icosahedral capsid morphology, and a triangulation number that is pseudo 7. Differential gene splicing is used by polyomaviruses to generate multiple transcripts (2 for SV40 and 3 for polyomavirus).
SV40, a simian polyomavirus that has been the most closely studied, contains three capsid proteins that are expressed by late genes (VP1, VP2, and VP3). The icosahedron is composed of 360 VP1 subunits, although 420 would be needed for a true T = 7 triangulation number. SV40 is unique in that there are 72 pentameric capsomers, each containing 5 molecules of VP1, and yet there is 6-fold symmetry. It is believed that calcium ions help to stabilize pentamer-pentamer interactions such that intermittent hexons are not needed to stabilize the capsid. In SV40, early genes code for T antigen proteins (small, middle, and large). Large T antigen of SV40 has been found to bind to tumor-suppressor proteins Rb, p53, p107, and p300, thereby promoting tumor growth.
Only two polyomaviruses are known to cause disease in humans, JC virus (JCV) and BK virus (BKV). Both were named after the initials of patients of whom the virus was first isolated from. BKV was discovered from the urine of a renal allograft recipient. BKV is believed to be transmitted via virus shedding in the urine, aerosols, sexual activity, and tissue transplantation. Common infection occurs in early childhood (before the age of 10) and tumors have been seen in the immune compromised. BKV has been associated with mild respiratory disease or cystitis (bladder infection). However, most with BKV and JCV do not present clinical illness. BKV do establish latency in the kidneys and possibly B lymphocytes and the virus can be reactivated after many years. The cytopathic effects of BKV include cell swelling, pycnotic nuclei, and elongation of cytoplasm before lysis. BKV has also been associated with retinitis, nephritis, pneumonia, and encephalitis. Since clinical presentation of BKV usually involves the immune compromised, a decrease in immunosuppressive therapy would likely help BKV associated disease.
JCV was named after an individual who had Hodgkin’s disease with progressive multifocal leukoencephalopathy (PML) and the virus was isolated from brain tissue. The method of transmission is believed to be the same as with BKV and latency is believed to occur in the same cells as BKV, along with the bone marrow. Cytopathic effects associated with JCV include cell enlargement and shrinking of cytoplasmic processes. JCV is more common in late childhood (by age 14) and PML has been associated with reactivation of JCV in the immune compromised. PML is a demyelinating disease of the CNS that occurs worldwide. PML has been observed to be a complication of such diseases as Hodgkin’s disease, TB, AIDS, and immune suppression due to organ transplantation procedures. The pathology of PML include multifocal plaque lesions, which contain oligodendrocytes, macrophages, and deformed astrocytes. These lesions can be seen with MRI or CT scans, which are typically found at the junction between the white and grey matter. Clinically, PML causes muscle weakness, dementia, and problems with senses, particularly vision. The life expectancy for PML usually ranges from a month to a year, depending on the severity of the disease. Nucleoside analogs such as cytarabine have been used to treat PML by stopping JCV DNA replication, although most drugs have not been shown to be very effective.
Image of Polyomavirus Replication
Fields Virology, 4 th Edition
Polyomaviruses are first adsorbed and endocytosed by the host cell and transported to the nucleus. In the nucleus, the virus is uncoated and transcription and translation (T proteins) of early region mRNAs takes place. Viral DNA is then replicated and late region mRNAs are transcribe and translated (capsid proteins). The next generation of virions are assembled in the nucleus after which they are transported in vesicles and are released by cell membrane fusion exocytosis.
JC polyomavirus may be associated with colon cancer: Two scientists at Leahi Hospital in Hawaii used PCR analysis to determine the presence of JC DNA in the normal and tumor colon tissue of colon cancer patients. All eight patients tested positive for the viral DNA, indicating a possible cofactor involvement of the JC virus and colon cancer.
Duran A, Nerurkar V. “Association of polyomavirus JC with colon cancer.” Ethn Dis. 2005 Summer; 15 (3 Suppl 4): S4–78–9.
Polyomavirus may utilize a component of the ATM (ataxia telangiectasia mutated) kinase pathway to prolong the S phase of the cell cycle: Polyomavirus infection has been found to increase the level of ATM-S1981 of cells in vivo in addition to increasing ATM activity in vitro. Scientists at the Harvard Medical School demonstrated that polyomavirus replication may be greatly reduced by the introduction of caffeine (an ATM inhibitor) or by the use of ATM-knockout cells, indicating a link between ATM and the sustained length of the S phase of polyomavirus infected cells.
Dahl, You et al. “Induction and Utilization of an ATM Signaling Pathway by Polyomavirs.” Journal of Virology, October 2005, p. 13007-13017, Vol. 79, No. 20
JCV and BKV may be important cofactors in brain tumor pathogenesis: Italian scientists used PCR to detect the presence of JCV and BKV DNA in malignant human brain biopsies. 50% of the specimens studied tested positive for polyomavirus DNA, indicating a possible cofactor relationship.
Delbue, Pagaini, Guerini et al. “Distribution, characterization and significance of polyomavirus genomic sequences in tumors of the brain and its covering.” J Med Virol. 2005 Nov; 77 (3): 447-54.
Viral characteristics may play an important function in the pathogenisis of polyomavirus-associated interstitial nephropathy: A group of Italian researchers have reported a case of PVAN in a kidney transplant recipient in which the associated BK virus strain contained a rearranged transcription control region. This patient experienced subsequent renal failure and retransplantation followed. A BKV strain was then detected with archetypal TCR in association with asymptomatic reactivation
Azzi, De Santis et al. “BK virus regulatory region sequence deletions in a case of human polyomavirus associated nephropathy (PVAN) after kidney transplantation.” J Clin Virol. 2005 Sep 29; [Epub ahead of print}]
BK virus relies on an intact microtubule network to enter a host cell: Polyomaviruses are not enveloped and require functioning microtubule systems to infect cells. Researchers at Brown University have demonstrated that disassembly of microtubule structures impedes an initial BKV infection in cells. However, selective inhibition of actin components does not affect the entry of BKV into host cells, as is the case for JC virus.
Eash and Atwood. “Involvement of cytoskeletal components in BK virus infectious entry.” J Virol. 2005 Sep; 79 (18): 11734-41.
International Committee on Taxonomy of Viruses Database Page for Polyomavirus
CDC website on SV40, Polio Vaccine, and Cancer
NIH website on SV40 and Cancer
Bliss Temple’s 2004 Humans and Viruses Polyomaviridae Web Page
Comparison of Polyomaviridae and Papillomaviridae (Past Humans and Viruses Student)
Electron Micrograph of SV40
http://pathmicro.med.sc.edu/lecture/images/sv40.jpg
Flint SJ, Enquist LW, Krug RM, Rancaniello VR, Skalka AM. Principles of Virology: Molecular Biology, Pathogenesis, and Control. Washington: ASM; 2000.
Knipe DM, Howley PM, eds. Fields Virology, 4th ed. Philadelphia: Lippincott, Williams and Wilkins; 2001.
Ryan KJ, Ray CG. Sherris Medical Microbiology: an Introduction to Infectious Diseases. New York: McGraw-Hill; 2004.
Strauss, James H. and Ellen G. Viruses and Human Disease. Academic Press, San Diego, 2002.
Created by Jon Wong, November 2005
for Human Biology 115A: Humans and Viruses
Professor Robert Siegel
Stanford University