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Polyomavirus is the sole genus of viruses within the family Polyomaviridae. 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. 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).
There are four polyomaviruses found in humans: JC virus, which can infect the respiratory system, kidneys, or brain (sometimes causing the fatal progressive multifocal leukoencephalopathy in the latter case), and BK virus, which produces a mild respiratory infection and can affect the kidneys of immunosuppressed transplant patients. Both viruses are very widespread: approximately 80 percent of the adult population in the United States have antibodies to BK and JC. Two recently discovered polyomaviruses, KI (Karolinska Institute) and WU (Washington University) viruses, are closely related to each other and have been isolated from respiratory secretions.
The Simian vacuolating virus 40 replicates in the kidneys of monkeys without causing disease, but causes sarcomas in hamsters. It is unknown whether it can cause disease in humans, which has caused concern since the virus may have been introduced into the general population in the 1950s through a contaminated polio vaccine.
An avian polyomavirus sometimes referred to as the Budgerigar fledgling disease virus is a frequent cause of death among caged birds.
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 derives from three abbreviations: Pa for Papillomavirus, Po for Polyomavirus, and Va for "vacuolating".
Additional recommended knowledge
Prior to genome replication, the processes of viral attachment, entry and uncoating occur. Cellular receptors for polyomaviruses are currently unknown, however, attachment of polyomaviruses to host cells is mediated by viral protein 1 (VP1). This can be confirmed as anti-VP1 antibodies have been shown to prevent the binding of polyomavirus to host cells.
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. 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 ocurs. More frequently, they are released when the cell lyses due to the cytotoxicity of virus particles present in the infected cell.
The Polyoma Large and small T-Antigen
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 . 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 . 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 .
The Polyoma Middle T-Antigen
The Polyoma Middle T-Antigen is used in animal breast cancer model systems like the PYMT system where it ist coupled to the MMTV promotor. There it functions as an oncogene, while the tissue where the tumor develops is determined by the MMTV promotor.
The diagnosis of polyomavirus almost always occurs after the primary infection as it is either asymptomatic or sub-clinical. The most effective way to test weather there has been a past infection is to use haemagglutination inhibition to find if there are any corresponding antibodies to the virus . This however is not necessary in immunocompetent individuals as the latent polyomavirus poses no threat.
In cases of progressive multifocal leucoencephalopathy (PML) and associated tumors, were the reactivation of polyomavirus is suspected, PCR is used on a biopsy of the tissue to amplify the polyomavirus DNA. This allows not only the detection of polyomavirus but also which sub type it is . ELISA-based assays for larg T-Antigen and small T-Antigen are also used to detect the level of expression and thus weather reactivation has occurred .
There are three main diagnostic techniques used for the diagnosis of the reactivation of polyomavirus in polyomavirus nephropathy (PVN): urine cytology, quantitation of the viral load in both urine and blood, and a renal biopsy . The reactivation of polyomavirus in the kidneys and urinary track 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 . Also as the urine of an infected individual will contain virions and/or viral DNA, quanitation of the viral load can be done done through PCR. 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.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Polyomavirus". A list of authors is available in Wikipedia.|