Polyomavirus
Encyclopedia
Polyomavirus is the sole genus
of virus
es within the family
Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross
in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals. 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).
The SV40 clade has a number of members:
The avian clade has two members:
The murine polyomavirus clade currently has three recognised members
Of these three only California sea lion polyomavirus has been associated with a lesion.
, BK virus
, KI virus and WU virus) are closely related to SV40 and infection with these viruses can be confused with SV40 infection. 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 monkey
s without causing disease, but causes sarcoma
s in hamster
s. 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. Most virologists find it unlikely that SV40 is circulating widely among humans and that is a major, if at all, cause for human cancers.
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.
(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.
, while the tissue where the tumor develops is determined by the MMTV promoter.
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.
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 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 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.
Tissue staining using a monoclonal antibody against MCV T antigen shows utility in differentiating Merkel cell carcinoma from other small, round cell tumors. 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.
These viruses have been found in breast
tumours. The importance of this finding - if any - is not known.
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...
of virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es within the family
Family (biology)
In biological classification, family is* a taxonomic rank. Other well-known ranks are life, domain, kingdom, phylum, class, order, genus, and species, with family fitting between order and genus. As for the other well-known ranks, there is the option of an immediately lower rank, indicated by the...
Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross
Ludwik Gross
Ludwik Gross was a Polish-American virologist who discovered two different tumor viruses, murine leukemia virus and mouse polyomavirus, capable of causing cancers in laboratory mice. Gross was born in Cracow, Poland to a prominent Jewish family and studied for a degree in medicine at the...
in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals. 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
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
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
SV40
SV40 is an abbreviation for Simian vacuolating virus 40 or Simian virus 40, a polyomavirus that is found in both monkeys and humans...
). 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
DNA virus
A DNA virus is a virus that has DNA as its genetic material and replicates using a DNA-dependent DNA polymerase. The nucleic acid is usually double-stranded DNA but may also be single-stranded DNA . DNA viruses belong to either Group I or Group II of the Baltimore classification system for viruses...
(double-stranded DNA, ~5000 base pairs, circular genome), small (40-50 nanometers in diameter), and icosahedral
Icosahedron
In geometry, an icosahedron is a regular polyhedron with 20 identical equilateral triangular faces, 30 edges and 12 vertices. It is one of the five Platonic solids....
in shape, and do not have a lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
envelope. Moreover, the genome possess early and late genes, contributing to its complex transcription program. They are potentially oncogenic (tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
-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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. 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
Papillomavirus
Papillomaviridae is an ancient taxonomic family of non-enveloped DNA viruses, collectively known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected birds and mammals, but also a small number...
which is now assigned to its own family Papillomaviridae
Papillomaviridae
Papillomaviridae is an ancient taxonomic family of non-enveloped DNA viruses, collectively known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected birds and mammals, but also a small number...
). 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
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...
(JC virus
JC virus
The JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
), nephropathy
Nephropathy
Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.-Causes:Causes of nephropathy include administration of analgesics, xanthine oxidase deficiency, and long-term exposure to lead or its salts...
(BK virus
BK virus
The BK virus is a member of the polyomavirus family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon, with the exception of the immunocompromised and the immunosuppressed.-History:...
), and Merkel cell cancer
Merkel cell cancer
Merkel cell carcinoma Merkel cell carcinoma Merkel cell carcinoma (also known as a "Cutaneous apudoma," "Primary neuroendocrine carcinoma of the skin," "Primary small cell carcinoma of the skin," and "Trabecular carcinoma of the skin"...
(Merkel cell virus).
Classification
Polyomaviruses are divided into three major clades (genetically-related groups): Many of the known viruses do not fall into these clades and the taxonomy of this family is on going.- SV40 clade
- an avian clade
- murine polyomavirus clade
The SV40 clade has a number of members:
- SV40
- JC polyomavirus
- BK polyomavirus
- SA12
The avian clade has two members:
- avian polyomavirus (causes Budgerigar Fledgling disease)
- goose hemorrhagic polyomavirus
The murine polyomavirus clade currently has three recognised members
- California sea lion polyomavirus 1
- Murine pneumotropic virus
- Squirrel monkey polyomavirus
Of these three only California sea lion polyomavirus has been associated with a lesion.
Genome
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.Human Polyomaviruses
Nine polyomaviruses have been found in humans. Four of these viruses (JC virusJC virus
The JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
, BK virus
BK virus
The BK virus is a member of the polyomavirus family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon, with the exception of the immunocompromised and the immunosuppressed.-History:...
, KI virus and WU virus) are closely related to SV40 and infection with these viruses can be confused with SV40 infection. Merkel cell polyomavirus
Merkel cell polyomavirus
Merkel cell polyomavirus was first described in January 2008. MCV is one of seven known human tumor viruses. It is suspected to cause the majority of cases of Merkel cell carcinoma, a rare but aggressive form of skin cancer. Approximately 80% of Merkel cell carcinoma tumors have been found to be...
(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).
- JC virusJC virusThe JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
can infect the respiratory systemRespiratory systemThe respiratory system is the anatomical system of an organism that introduces respiratory gases to the interior and performs gas exchange. In humans and other mammals, the anatomical features of the respiratory system include airways, lungs, and the respiratory muscles...
, kidneys, or brainHuman brainThe human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
(sometimes causing the fatal progressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...
in the latter case).
- BK virusBK virusThe BK virus is a member of the polyomavirus family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon, with the exception of the immunocompromised and the immunosuppressed.-History:...
produces a mild respiratory infection and can affect the kidneys of immunosuppressed transplantOrgan transplantOrgan transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
patients. Both of these viruses are very widespread: approximately 80 percent of the adult population in the United StatesUnited StatesThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
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 2010, two additional viruses related to KI and WU were identified in human skin secretions.
- In January 2008, a new virus, Merkel cell polyomavirusMerkel cell polyomavirusMerkel cell polyomavirus was first described in January 2008. MCV is one of seven known human tumor viruses. It is suspected to cause the majority of cases of Merkel cell carcinoma, a rare but aggressive form of skin cancer. Approximately 80% of Merkel cell carcinoma tumors have been found to be...
, was described and shown to cause most Merkel skin cancerMerkel cell carcinomaMerkel cell carcinoma Merkel cell carcinoma Merkel cell carcinoma (also known as a "Cutaneous apudoma," "Primary neuroendocrine carcinoma of the skin," "Primary small cell carcinoma of the skin," and "Trabecular carcinoma of the skin"...
.
- In August, 2010, a sixth polyoma virus, trichodysplasia spinulosa-associated polyomavirus (TSV), was discovered in the proliferative skin lesion termed trichodysplasia spinulosa seen in immunosuppressed patients.
- In March, 2011, a ninth polyoma virus HPyV9, related to a monkey lymphotropic virus (LPV) was cultured from the blood of immunosuppressed patients. The finding partially explains why some humans had antisera cross reactive with monkey LPV but none of the known human polyomaviruses cross-reacted with those patient's sera.
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
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
, old age or after transplantation and include Merkel cell carcinoma
Merkel cell carcinoma
Merkel cell carcinoma Merkel cell carcinoma Merkel cell carcinoma (also known as a "Cutaneous apudoma," "Primary neuroendocrine carcinoma of the skin," "Primary small cell carcinoma of the skin," and "Trabecular carcinoma of the skin"...
, PML
PML
PML may refer to:* Pakistan Muslim League, faction of the Pakistani political parties with similar names* Partido Movimiento Libertario, libertarian political party in Costa Rica* Perfectly Matched Layer, numerical truncation methodology....
and BK nephropathy.
The SV40 replicates in the kidneys of monkey
Monkey
A monkey is a primate, either an Old World monkey or a New World monkey. There are about 260 known living species of monkey. Many are arboreal, although there are species that live primarily on the ground, such as baboons. Monkeys are generally considered to be intelligent. Unlike apes, monkeys...
s without causing disease, but causes sarcoma
Sarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
s in hamster
Hamster
Hamsters are rodents belonging to the subfamily Cricetinae. The subfamily contains about 25 species, classified in six or seven genera....
s. 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
Polio vaccine
Two polio vaccines are used throughout the world to combat poliomyelitis . The first was developed by Jonas Salk and first tested in 1952. Announced to the world by Salk on April 12, 1955, it consists of an injected dose of inactivated poliovirus. An oral vaccine was developed by Albert Sabin...
. 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. Most virologists find it unlikely that SV40 is circulating widely among humans and that is a major, if at all, cause for human cancers.
Replication
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.Polyomavirus virions are subsequently endocytosed
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
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
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
of the host. They are able to utilise the host’s machinery because the genomic
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
structure is homologous
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
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
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
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
SV40 Large T-antigen
SV40 large T antigen is a hexamer protein that is a proto-oncogene derived from the polyomavirus SV40 which is capable of transforming a variety of cell types. The transforming activity of TAg is due in large part to its perturbation of the retinoblastoma and p53 tumor suppressor proteins...
). 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
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA 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
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, where budding
Budding
Budding is a form of asexual reproduction in which a new organism grows on another one. The new organism remains attached as it grows, separating from the parent organism only when it is mature. Since the reproduction is asexual, the newly created organism is a clone and is genetically identical...
occurs. More frequently, they are released when the cell lyses
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
due to the cytotoxicity
Cytotoxicity
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
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 retinoblastomaRetinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
(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 is coupled to the MMTV promoter. There it functions as an oncogeneOncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
, while the tissue where the tumor develops is determined by the MMTV promoter.
Agnoprotein
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.Diagnosis
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. Competition assays are frequently needed to distinguish among highly similar polyomaviruses.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
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
to amplify the polyomavirus DNA. This allows not only the detection of polyomavirus but also which sub type it is.
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
Renal biopsy
A renal biopsy is a procedure in which a sample of kidney tissue is obtained. Microscopic examination of the tissue can provide information needed to diagnose, monitor or treat a renal disorder.-Indications:...
.
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. 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. 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. 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.
These viruses have been found in breast
Breast
The breast is the upper ventral region of the torso of a primate, in left and right sides, which in a female contains the mammary gland that secretes milk used to feed infants.Both men and women develop breasts from the same embryological tissues...
tumours. The importance of this finding - if any - is not known.