Human JC Polyomavirus
A Microbial Biorealm page on the genus Human JC Polyomavirus
Higher order taxa
Viruses; dsDNA viruses, no RNA stage; Polyomaviridae; Polyomavirus
Description and significance
The JC virus was first isolated from a brain in a patient with Hodgkin’s disease in 1971. The patient was also suffering from Progressive multifocal leaukoencephalopathy(PML). The virus is named after the patient’s initials. The JC virus is a double-stranded DNA virus. It is strictly a human virus whose viral chromosome structure is very similar to its host chromatin.(5) JC virus have a very simple genome. Inside its human host it can establish three kinds of infections: latent, persistent, and active infections. The infections are established depending on the strength of the host’s immune system, and the tissue type that is infected.(7) Latent infections occur in the kidney tissue. Persistent infections occur in renal proximal tubule cells, and active infections occur in the oligodendrocyte glial cells in the central nervous system.(8) These cells specifically support replication of the virus. Active infections destroy oligodendrocytes and lead to a disease known as Progressive multifocal leaukoencephalopathy (PML).(7) The JC virus infection is extremely widespread, and currently there is no cure for when the virus become active.
The JC virus genome consists of a single double stranded DNA molecule. Their DNA is a covalently closed, superhelical, circular molecule and assembled in a set of about 21 nucleosomes.(5) There are four cellular histones associated with the DNA. H2A, H2B, H3, and H4 cellular histone are in the form of chromatin. They control transcription after infection. Two copies of each histone are contained within each of the 21 nucleosomes. The genome consists of 5.130 nucleotide base pairs long.(1) The circular molecule contains an early transcription unit region and a late transcription unit region and a non-coding region. The non-coding region is the viral regulatory region and includes an origin of replication, that both regions are initiated by, and bidirectional promoters and enhancers that control transcription.(9) The two transcription units code for a total of six genes in the genome. The early transcription unit extends from the origin to half way around the circular genome and encodes alternatively spliced transforming proteins.(7) These proteins are large T antigens and small t antigens. They are considered the viral regulatory proteins and share common N-terminal sequences but have different C-terminal sequences. The late transcription unit encodes the three structural capsid proteins, VP1 major capsid protein and minor capsid proteins VP2 and VP3. The coding sequences of VP2 and VP3 overlap with the entire sequence of the VP3 contained within the VP2’s C-terminus. The N-terminus of VP1 overlaps with VP2 and VP3 at their C-terminus. It consists of alternately spliced mRNAs.(9) It also encodes in its leader region a small late protein called the agnoprotein that functions in the transporting of the capsid proteins to the nucleus.
Virion structure and Reproduction Cycle
The JC virus is a 45 nm in diameter, non-enveloped, icosahedral virus. The single molecule of double-stranded DNA is enclosed inside a capsid. Three virus encoded proteins are contained in the capsid. VP1, VP2, VP3 capsid proteins are arranged in 72 pentameric capsomers and form a T=7 isosahedral capsid. The virion contains 360 copies of VP1 protein, and the surface of each VP1 protein contains a sialic acid binding site. There are 30 and 60 VP2 and VP3 proteins in each virion.(7)
Reproduction Cycle of the JC virus in a Host Cell
Infection of the JC virus is divided into an early and a late stage. In the early stage the JC virus attaches to the host cell by receptors containing sialic acid. The VP1 capsid protein is responsible for receptor binding.(6) VP2 and VP3 capsid proteins facilitate entry and uncoating. The virions are taken up by receptor mediated endocytosis and are transported to the nucleus by interaction of endocytic vacuoles with the cytoskeleton. They enter the host nucleus through the nuclear pores and uncoat inside. The virus cellular histones are transcribed by host RNA polymerase II into early mRNAs which are translated into the early antigen protein. In the late stage the viral DNA is replicated with enzymes produced by the T antigens. The DNA is then translated to produce late mRNAs which are translated into the capsid proteins, VP1, VP2, and VP3. The progeny virions are then assembled inside the nucleus and the newly assembled virions enter into the cytoplasmic vesicles. The cytoplasmic vesicles fuse with the plasma membrane releasing virions from the cell.(7) This active infection occurs in the replication supporting cells inside the host. If the host cells are not permissive then only the early stage is carried out and the infection does not become active.(7)
Ecology and Pathology
JC virus exposure and infection usually occurs at an early age in humans. The infection is widespread it is estimated that 50-80% of adults have antibodies to the JC virus indicating the exposure and/or presence of the JC virus. Transmission of the virus is still not completely understood but evidence of respiratory transmission had been found. Alternative modes of transmission are still being researched.(2)
Persistent infections occur in the cells of the kidneys and of the urinary tract in healthy individuals. The immune system in healthy individuals is able to clear infection causing the virus to establish latent infections. In active infection, viral DNA replication can undergo transformation. The T antigens are the viral proteins responsible for the transformation. Infected cells carry the virus containing transformed DNA to the brain. Once the virus reaches the oligodendrocytes in the brain, a highly productive infection is initiated.(3) Active infections occur when the JC virus becomes reactivated in permissive cells of immunosuppressed individuals that have a decrease in the amount of immune system cells, especially the CD34+ cells. AIDS is a major cause of reactivation of the JC virus. JC virus enters into a lytic active infection of the oligodendrocyte glial cells in the brain. These cells are the myelin producing cells of the brain. The infection causes dymyelination of these cells leading to lesions in the brain.(7)
PML results from this infection, and is a fatal disease. PML first, evolves slowly, and the loss of brain functions occurs at a similar rate. Impairment in vision and speech and often movement start to occur. Once PML starts to progress rapidly these symptoms become more severe leading to blindness and paralyzation and eventually coma and death.(5) The life expectancy of a patient with PML is between several months and 1 year depending on the severity of the immune system deficiency. Additional from predisposing immune disorders, liver and heart transplant have also been linked to the onset of PML.
In active infection, viral DNA replication can undergo transformation. The T antigens are the viral proteins responsible for the transformation. Infected cells carry the virus containing transformed DNA to the brain. Once the virus reaches the oligodendrocytes in the brain, a highly productive infection is initiated.(7)
Research of the JC virus is ongoing and continuously growing. Many things are still unknown and not understood about the JC virus. It is still unclear how the virus is spread throughout the population and how the virus persists in healthy individuals. Studies to pursue immune responses to the JC virus have involved using animal models. This use of study is not completely reliable because the genetic structure of the human and animal virus is different.(4) Advancements in genetics are being researched particularly in gene-amplification-based assays like PCR that can detect JC virus DNA in tissues. Research for treatment of PML is of great importance and interest and is extensively ongoing.
Nucleotide analogs are being administered to block JC virus DNA replication. Cytarabine is one such analog and has been administered intrathecally and intravenously. This analog still does not show remarkable clinical improvements or consistency in the results. Antiviral drugs and therapy are being developed and tested for efficacy. Delayment of the progression of the disease is linked to the antiviral drug, cidovofir and cell cultures are being used to target drug treatment sites by identifying elements involved in blocking DNA replication.(7) Highly active antiretroviral therapy (HAART) is being tested on individuals with AIDS and has shown declines in the number of incidences of PML in individuals with AIDS.(7)
1. Frisque, Richard J., Bream, Gary L., and Cannella, Maria T., 1984. Human Polyamovirus JC Virus Genome. Journal of Virology v.51, p.458-469.
2. Gasparovic, M. L., Gee, G. V., and Atwood, W.J., 2006. JC Virus Minor Capsid Proteins Vp2 and Vp3 Are Essential for Virus Propagation. Journal of Virology v. 80,p.10858- 10861.
3. Henson, John W., 1994. Regulation of the Glial-Specific JC Virus Early Promoter by the Transcription Factor Sp1. The Journal of Biological Chemistry v.269, p.1046-1050.
4. Jiang, Mengxi, Abend, Johanna R., Johnson, Silas F., and Imperiale, Michael J., 2008.The role of polyomaviruses in human disease. Virology, p. 1-8.
5. Kim, So-Young, Woo, Moon-Sook, Kim, Won-Ki, Choi, Eung-Chil, Henson, John W.,and Kim, Hee-Sun. 2003. Glial Cell-Specific Regulation of the JC Virus Early Promoter by Histone Deacetylase Inhibitors. Journal of Virology v. 77, p. 3394-33401.
6. Lui, Christine K., Wei, Grant, and Atwood, Walter J., 1998. Infection of the Glial Cells by Human Polyomavirus JC Is Mediated by and N-Linked Glycoprotein Containing Terminal alpha(2-6)- Linked Sialic Acids. Journal of Virology v.72,p. 4643-4649.
7. Major, Eugene O., 2001. Human Polyomavirus, p.2175-2196. Fields Virology. Lippincott Williams and Wilkins, Philadelphia, 3087.
8. Major, E. O., Amemiya, K., Tornatore, C. S., Houff, S. A., and Berger, J. R., 1992. Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clinical Microbiology Reviews v. 5, p. 49-73.
9. White, Martyn K., and Khalili, Kamel. 2004. Polyomavirus and human cancer: molecular mechanisms underlying patterns of tumorigenesis. Virology v. 324, p. 1-16.
Edited by Rachel Marie Clay a student of Emily Lilly at University of Massachusetts Dartmouth.