Everything about Polyomaviridae totally explained
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 don't 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).
Five polyomaviruses have been found in humans.
JC virus can infect the
respiratory system,
kidneys, or
brain (sometimes causing the fatal
progressive multifocal leukoencephalopathy in the latter case).
BK virus produces a mild respiratory infection and can affect the kidneys of immunosuppressed
transplant patients. Both of these 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. In January 2008, a new species,
Merkel cell polyomavirus, was described as the likely causative agent of
Merkel skin cancer.
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".
Replication
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.
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Polyomavirus virions are subsequently
endocytosed and transported directly to the nucleus in endocytic
vacuoles where uncoating occurs.
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're transported in cytoplasmic vacuoles to the
plasma membrane, where
budding ocurs. More frequently, they're 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's coupled to the
MMTV promoter. There it functions as an
oncogene, while the tissue where the tumor develops is determined by the MMTV promoter.
Diagnosis
The diagnosis of polyomavirus almost always occurs after the primary infection as it's either asymptomatic or sub-clinical. The most effective way to test whether there has been a past infection is to use haemagglutination inhibition to find if there are any corresponding antibodies to the virus . This however isn't necessary in immunocompetent individuals as the latent polyomavirus poses no threat.
In cases of progressive multifocal leucoencephalopathy (PML) and associated tumors, where the reactivation of polyomavirus is suspected, PCR is 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's . ELISA-based assays for large T-Antigen and small T-Antigen are also used to detect the level of expression and thus whether reactivation has occurred .
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 .
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's 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.
Further Information
Get more info on 'Polyomaviridae'.
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