Important properties of polyomaviruses are listed in Table 1. Classification The Polyomaviridae family contains a single genus designated Polyomavirus, formerly part of the Papovaviridae family (which no longer exists). Polyomaviruses are small viruses (diameter 45 nm) that possess a circular genome of double stranded DNA (5 kbp; molecular weight 3 × 10⁶) enclosed within a nonenveloped capsid exhibiting icosahedral symmetry (Figure 1). Cellular histones are used to con dense viral DNA inside virus particles.

Table1. Important Properties of Polyomaviruses ^a

Fig1. Polyomavirus SV40. Purified preparation negatively stained with phosphotungstate (150,000×). (Courtesy of S McGregor and H Mayor.)

Polyomaviruses are simple DNA-containing viruses that possess a limited amount of genetic information (six or seven genes). Multiple species have been identified, including the tumor virus SV40 and others known to infect humans (BK, JC, KI, WU, MCV, HPyV6, HPyV7, HPyV10, and TSV). Many species of mammals and some birds have been found to carry their own species of polyomavirus.

Polyomavirus Replication

 The polyomavirus genome contains “early” and “late” regions (Figure 2). The early region is expressed soon after infection of cells; it contains genes that code for early proteins— for example, the SV40 large tumor (T) antigen, which is necessary for the replication of viral DNA in permissive cells, and the small tumor (t) antigen. The murine polyoma virus genome encodes three early proteins (small, middle, and large T antigens). One or two of the T antigens are the only viral gene products required for transformation of cells. Usually, the transforming proteins must be continuously synthesized for cells to stay transformed. The late region consists of genes that code for the synthesis of coat protein; they have no role in transformation and usually are not expressed in transformed cells.

Fig2. Genetic map of the polyomavirus SV40. The thick circle represents the circular SV40 DNA genome. The unique EcoRI site is shown at map unit 0/1. Nucleotide numbers begin and end at the origin (Ori) of viral DNA replication (0/5243). Boxed arrows indicate the open reading frames that encode the viral proteins. Arrowheads point in the direction of transcription; the beginning and end of each open reading frame are indicated by nucleotide numbers. Various shadings depict different reading frames used for different viral polypeptides. Note that large T antigen (T-ag) is coded by two noncontiguous segments on the genome. The genome is divided into “early” and “late” regions that are expressed before and after the onset of viral DNA replication, respectively. Only the early region is expressed in transformed cells. (Reproduced with permission from Butel JS, Jarvis DL: The plasma-membrane associated form of SV40 large tumor antigen: Biochemical and biological properties. Biochim Biophys Acta 1986;865:171.)

SV40 T antigen interacts with the cellular tumor sup pressor gene products, p53 and pRb family members (see Table 2). Interactions of T antigen with the cellular proteins are important in the replicative cycle of the virus. This com plex formation functionally inactivates the growth-inhibitory properties of pRb and p53, allowing cells to enter S phase so that viral DNA may be replicated. Likewise, functional inactivation of the cellular proteins by T antigen binding is central to the virus-mediated transformation process. As p53 senses DNA damage and either blocks cell cycle progression or initiates apoptosis, abolishing its function would lead to accumulation of T antigen-expressing cells with genomic mutations that might promote tumorigenic growth.

Table2. Examples of DNA Virus Oncoproteins and Cellular Protein Interactions ^a

Pathogenesis and Pathology

The human polyomaviruses BK and JC are widely distributed in human populations, as evidenced by the presence of specific antibody in 70–80% of adult sera. Infection usually occurs during early childhood. Both viruses may persist in the kidneys and lymphoid tissues of healthy individuals after primary infection and may reactivate when the host’s immune response is impaired, for example, by renal transplantation, during pregnancy, or with increasing age. Viral reactivation and shedding in urine are asymptomatic in immunocompetent persons. The viruses are most commonly isolated from immunocompromised patients, in whom disease may occur. BK virus causes hemorrhagic cystitis in bone marrow transplant recipients. It is the cause of polyomavirus-associated nephropathy in renal trans plant recipients, a serious disease that occurs in up to 5% of recipients and results in graft failure in up to 50% of those affected patients. JC virus is the cause of progressive multifocal leukoencephalopathy, a fatal brain disease that occurs in some immunocompromised persons, especially those with depressed cell-mediated immunity resulting from immunosuppressive therapies or infection by HIV. Progressive multifocal leukoencephalopathy affects about 5% of AIDS patients. BK and JC viruses are antigenically distinct, but both encode a T antigen that is related to SV40 T antigen. These human viruses can transform rodent cells and induce tumors in newborn hamsters. JC virus has been associated with human brain tumors, but an etiologic role is not yet established.

KI and WU viruses were discovered in 2007 in nasopharyngeal aspirates from children with respiratory infections. Merkel cell polyomavirus was identified in 2008 in Merkel cell carcinomas, rare skin tumors of neuroendocrine origin. Seroprevalence studies suggest that KI, WU, and Merkel cell virus infections are common and widespread and occur in childhood. HPyV6, HPyV7, and HPyV10 appear to be constituents of human skin. Trichodysplasia spinulosa–associated polyomavirus (TSV) was discovered in proliferative skin lesions, HPyV9 was found in the blood of immunosuppressed patients, and HPyV12 was found in liver tissue. Other polyomaviruses have been found in human stool, including MWPyV and STL polyomavirus. Because of their recent discoveries, information on disease associations is limited.

Merkel cell virus appears to be etiologically important in a large fraction of Merkel cell carcinomas. In many of the tumors characterized, Merkel cell virus DNA is clonally integrated in tumor cells, oncogene expression is required for cell growth, and the integrated viral genomes have mutations in the T antigen gene that prevent viral DNA replication.

SV40 replicates in certain types of monkey and human cells; it is highly tumorigenic in experimentally inoculated hamsters and in transgenic mice and can transform many types of cells in culture. Tumor induction in the natural host—the rhesus monkey—is rarely observed. SV40 may cause a progressive multifocal leukoencephalopathy-like dis ease in rhesus monkeys.

SV40 contaminated early lots of live and killed poliovirus vaccines that had been grown in monkey cells unknowingly infected with SV40. Millions of people worldwide received such SV40-contaminated vaccines between 1955 and 1963. SV40 is detected in humans today, including in individuals too young to have been exposed via vaccination. Evidence suggests that it (and other polyomaviruses) may be trans mitted by the fecal–oral route in humans. The prevalence of SV40 infections in humans appears to be low.

SV40 DNA has been detected in selected types of human tumors, including brain tumors, mesotheliomas, bone tumors, and lymphomas. The role SV40 may be playing in formation of human cancers is unknown.

The host range for polyomaviruses is often highly restricted. Usually, a single species can be infected and only certain cell types within that species. Exceptions are the primate polyomaviruses SV40 and BK virus; SV40 can also infect humans and human cells, and BK virus can infect some monkeys and monkey cells.

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مواضيع ذات صلة

Structure and Composition of Lentiviruses

HERPESVIRUSES

Human T-Lymphotropic Viruses

Replication of Retroviruses

Classification of Retroviruses

Interactions of Tumor Viruses with Their Hosts

PAPILLOMAVIRUSES

General Features of Viral Carcinogenesis

Immunity and Prevention of Rabies Virus

Methods of Antiviral Susceptibility Testing: Influenza

Methods of Antiviral Susceptibility Testing: Genotypic Susceptibility Assays

Methods of Antiviral Susceptibility Testing: Phenotypic Assays