| Polyomavirus | |
|---|---|
| Micrograph showing a polyomavirus infected cell - large (blue) cell below-center-left. Urine cytology specimen. | |
| Virus classification | |
| Group: | Group I (dsDNA) |
| Family: | Polyomaviridae |
| Genus: | Polyomavirus |
| Species | |
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African green monkey polyomavirus |
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Polyomavirus is the sole genus of viruses within the family Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross in 1953.[1] Subsequently, many polyomaviruses have been found to infect birds and mammals. For nearly 40 years, only two polyomaviruses were known to infect humans. Genome sequencing technologies have recently discovered seven additional human polyomaviruses, including one causing most cases of Merkel cell carcinoma and another associated with transplant-associated dysplasia (TSV), that are natural infections of humans. Discovery of these polyomaviruses and other new--but previously undiscovered--viruses may provide clues to the etiologies for human diseases. Polyomaviruses have been extensively studied as tumor viruses in humans and animals, leading to fundamental insights into carcinogenesis, DNA replication and protein processing. The tumor suppressor molecule p53 was discovered, for example, as a cellular protein bound by the major oncoprotein (cancer-causing protein) T antigen made by Simian vacuolating virus 40 (SV40). The avian polyomavirus sometimes referred to as the Budgerigar fledgling disease virus is a frequent cause of death among caged birds.
Polyomaviruses are DNA-based (double-stranded DNA, ~5000 base pairs, circular genome), small (40-50 nanometers in diameter), and icosahedral in shape, and do not have a lipoprotein envelope. Moreover, the genome possess early and late genes, contributing to its complex transcription program. They are potentially oncogenic (tumor-causing); they often persist as latent infections in a host without causing disease, but may produce tumors in a host of a different species, or a host with an ineffective immune system. The name polyoma refers to the viruses' ability to produce multiple (poly-) tumors (-oma).
The genus Polyomavirus used to be one of two genera within the now obsolete family Papovaviridae (the other genus being Papillomavirus which is now assigned to its own family Papillomaviridae). The name Papovaviridae derived from three abbreviations: Pa for Papillomavirus, Po for Polyomavirus, and Va for "vacuolating". Clinically, Polyomaviridæ are relevant as they contribute to pathologies such as Progressive multifocal leukoencephalopathy (JC virus), nephropathy (BK virus), and Merkel cell cancer (Merkel cell virus).
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Polyomaviruses are divided into three major clades (genetically-related groups):[2] Many of the known viruses do not fall into these clades and the taxonomy of this family is on going.
The SV40 clade has a number of members:
The avian clade has two members:
The murine polyomavirus clade currently has three recognised members[4]
Of these three only California sea lion polyomavirus has been associated with a lesion.
The genome is circular, composed of double stranded DNA and has six genes: large T, small t, viral protein 1 (VP1), viral protein 2 (VP2), and viral protein 3 (VP3) and agnoprotein. It is about 5 kilobase pairs in length. VP1-3 form the viral capsid.
Nine polyomaviruses have been found in humans. Four of these viruses (JC virus, BK virus, KI virus and WU virus) are closely related to SV40 and infection with these viruses can be confused with SV40 infection.[5][6] Merkel cell polyomavirus (MCV) is highly divergent from the other human polyomaviruses and is most closely related to murine polyomavirus. Trichodysplasia spinulosa-associated polyomavirus (TSV), is distantly related to MCV. Two viruses - HPyV6 and HPyV7 - are most closely related to KI and WU viruses, while HPyV9 is most closely related to the African green monkey-derived lymphotropic polyomavirus (LPV).
All the polyomaviruses are highly common childhood and young adult infections. Most of these infections appear to cause little or no symptoms. These viruses are probably life-long persistent among almost all adults. Diseases caused by human polyomavirus infections are most common among persons who become immunosuppressed by AIDS, old age or after transplantation and include Merkel cell carcinoma, PML and BK nephropathy.
The SV40 replicates in the kidneys of monkeys without causing disease, but causes sarcomas in hamsters. It is highly controversial whether it can cause disease in humans since the virus may have been introduced into the general population in the 1950s through a contaminated polio vaccine. Thus far, no widely-accepted evidence for the virus being present in human cancer has been reported although reports for it being present in pleural mesothelioma, some nonHodgkin's lymphomas and other human cancers have been published. This is confounded by the high level of cross-reactivity for SV40 with known human polyomaviruses (BK virus and JC virus) that are widespread and by common use of SV40 DNA as a near universal reagent in scientific laboratories.[6] Most virologists dismiss SV40 as a cause for human cancers.[5]
Prior to genome replication, the processes of viral attachment, entry and uncoating occur. Cellular receptors for polyomaviruses are sialic acid residues of gangliosides. The attachment of polyomaviruses to host cells is mediated by viral protein 1 (VP1) via the sialic acid attachment region. This can be confirmed as anti-VP1 antibodies have been shown to prevent the binding of polyomavirus to host cells.[16]
Polyomavirus virions are subsequently endocytosed and transported first to the endoplasmatic reticulum where a conformational change occurs revealing Vp2. Then by an unknown mechanism the virus is exported to the nucleus.
Polyomaviruses replicate in the nucleus of the host. They are able to utilise the host’s machinery because the genomic structure is homologous to that of the mammalian host. Moreover, the promoter sequence of Polyomavirus' promoter sequence is a strong attractant for the host's RNAP. Viral replication occurs in two distinct phases; early and late gene expression, separated by genome replication.
Early gene expression is responsible for the synthesis of non-structural proteins. Since Polyomaviruses rely on the host to control both the gene expression, the role of the non-structural proteins is to regulate the cellular mechanisms. Close to the N terminal end of polyomavirus genome are enhancer elements which induce activation and transcription of a molecule known as the T-antigen (see SV40 Large T-antigen). Early mRNA’s, encoding T-antigen are produced by host RNA polymerase II. T-antigen autoregulates early mRNA’s, subsequently leading to elevated levels of T-antigen. At high concentrations of T-antigen, early gene expression is repressed, triggering the late phase of viral infection to begin.
Genome replication acts to separate the early and late phase gene expression. The duplicated viral genome is synthesised and processed as if it were cellular DNA, exploiting the host’s machinery. As the daughter viral DNA are synthesised they associate with cellular nucleosomes to form structures that are often referred to as "minichromosomes". In this manner the DNA is packaged more efficiently.
Late gene expression synthesises the structural proteins, responsible for the viral particle composition. This occurs during and after genome replication. As with the early gene expression products, late gene expression generates an array of proteins as a result of alternative splicing.
Within each viral protein are 'nuclear localization signals' which cause the viral proteins to amass in the nucleus. Assembly of new virus particles consequently occurs within the nucleus of the host cell.
Release of newly synthesized polyomavirus particles exit the infected cell by one of two mechanisms. Firstly and less commonly, they are transported in cytoplasmic vacuoles to the plasma membrane, where budding occurs. More frequently, they are released when the cell lyses due to the cytotoxicity of virus particles present in the infected cell.
The large T-antigen plays a key role in regulating the viral life cycle by binding to the viral origin of DNA replication where it promotes DNA synthesis. Also as the polyomavirus relies on the host cell machinery to replicate the host cell needs to be in s-phase for this to begin. Due to this, large T-antigen also modulates cellular signaling pathways to stimulate progression of the cell cycle by binding to a number of cellular control proteins.[17] This is achieved by a two prong attack of inhibiting tumor suppressing genes p53 and members of the retinoblastoma (pRB) family, and stimulating cell growth pathways by binding cellular DNA, ATPase-helicase, DNA polymerase α association, and binding of transcription preinitiation complex factors.[18] This abnormal stimulation of the cell cycle is a powerful force for oncogenic transformation.
The small T-antigen protein is also able to activate several cellular pathways which stimulate cell proliferation. Such as the mitogen-activated protein kinase (MAPK) pathway, and the stress-activated protein kinase (SAPK) pathway.[19][20]
The Polyoma Middle T-Antigen is used in animal breast cancer model systems like the PYMT system where it is coupled to the MMTV promoter. There it functions as an oncogene, while the tissue where the tumor develops is determined by the MMTV promoter.
The agnoprotein is a small multifunctional phospho-protein found in the late coding part of the genome. It appears to be involved in DNA replication but the exact mechanism remains unclear.[21]
The diagnosis of polyomavirus almost always occurs after the primary infection as it is either asymptomatic or sub-clinical. Antibody assays are commonly used to detect presence of antibodies against individual viruses.[22] Competition assays are frequently needed to distinguish among highly similar polyomaviruses.[23]
In cases of progressive multifocal leucoencephalopathy (PML), a cross-reactive antibody to SV40 T antigen (commonly Pab419) is used to stain tissues directly for the presence of JC virus T antigen. PCR can be used on a biopsy of the tissue or cerebrospinal fluid to amplify the polyomavirus DNA. This allows not only the detection of polyomavirus but also which sub type it is.[24]
There are three main diagnostic techniques used for the diagnosis of the reactivation of polyomavirus in polyomavirus nephropathy (PVN): urine cytology, quantification of the viral load in both urine and blood, and a renal biopsy.[22] The reactivation of polyomavirus in the kidneys and urinary tract causes the shedding of infected cells, virions, and/or viral proteins in the urine. This allows urine cytology to examine these cells, which if there is polyomavirus inclusion of the nucleus, is diagnostic of infection.[25] Also as the urine of an infected individual will contain virions and/or viral DNA, quanitation of the viral load can be done through PCR.[26] This is also true for the blood.
Renal biopsy can also be used if the two methods just described are inconclusive or if the specific viral load for the renal tissue is desired. Similarly to the urine cytology, the renal cells are examined under light microscopy for polyomavirus inclusion of the nucleus, as well as cell lysis and viral partials in the extra cellular fluid. The viral load as before is also measure by PCR.
Tissue staining using a monoclonal antibody against MCV T antigen shows utility in differentiating Merkel cell carcinoma from other small, round cell tumors.[27] Blood tests to detect MCV antibodies have been developed and show that infection with the virus is widespread although Merkel cell carcinoma patients have exceptionally higher antibody responses than asymptomatically infected persons.[28][29][30][31]
These viruses have been found in breast tumours.[32] The importance of this finding - if any - is not known.
There is no known treatment for infection with these viruses. However it appears that some of fluoroquinolones may have theraptutic potential.[33]
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