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Oncogenic viruses (Human cancer viruses) Viruses are considered to be factors in the development of several types of human tumors. The viruses that have been strongly associated with human cancers are listed in Table 4. They include human papillomaviruses, Epstein-Barr virus, human herpesvirus 8, hepatitis B virus, hepatitis C virus, and two human retroviruses plus several candidate human cancer viruses. Many viruses can cause tumors in animals, either as a consequence of natural infection or after experimental inoculation. Table 4. Association of Viruses with Human Cancers.1 Virus Family Virus Human Cancer Papillomaviridae Human papillomaviruses Genital tumors Squamous cell carcinoma Oropharyngeal carcinoma Herpesviridae EB virus Human herpesvirus 8 Nasopharyngeal carcinoma Burkitt's lymphoma Hodgkin's disease B cell lymphoma Kaposi's sarcoma Hepadnaviridae Hepatitis B virus Hepatocellular carcinoma Retroviridae Adult T cell leukemia HTL virus Human AIDS-related malignancies immunodeficiency virus Flaviviridae Hepatitis C virus Hepatocellular carcinoma 1 Candidate human tumor viruses include additional types of papillomaviruses and polyomaviruses SV40, JC, and BK. EB, Epstein-Barr; HTL, human T-cell lymphoma. General Features of Viral Carcinogenesis These features are summarized in Table 5 Table 5 Features of Viral Carcinogenesis. 1. Viruses can cause cancer in animals and humans. 2. Tumor viruses frequently establish persistent infections in natural hosts. 3. Host factors tumorigenesis. are important determinants of virus-induced 4. Viruses are seldom complete carcinogens. 5. Virus infections are more common than virus-related tumor formation. 6. Long latent periods usually elapse between initial virus infection and tumor appearance. 7. Viral strains may differ in oncogenic potential. 8. Viruses may be either direct- or indirect-acting carcinogenic agents. 9. Oncogenic viruses modulate growth control pathways in cells. 10. Animal models may reveal mechanisms of viral carcinogenesis. 11. Viral markers are usually present in tumor cells. 12. One virus may be associated with more than one type of tumor. Tumor Viruses Are of Different Types Like other viruses, tumor viruses are classified among different virus families according to the nucleic acid of their genome and the biophysical characteristics of their virions. Most recognized tumor viruses either have a DNA genome . DNA tumor viruses are classified among the papilloma, polyoma-, adeno-, herpes-, hepadna-, and poxvirus groups. DNA tumor viruses encode viral oncoproteins that are important for viral replication but also affect cellular growth control pathways. Most RNA tumor viruses belong to the retrovirus family. Retroviruses carry an RNA-directed polymerase (reverse transcriptase) that constructs a DNA copy of the RNA genome of the virus. The DNA copy (provirus) becomes integrated into the DNA of the infected host cell, and it is from this integrated DNA copy that all proteins of the virus are translated. Multistep Carcinogenesis Carcinogenesis is a multistep process, ie, multiple genetic changes must occur to convert a normal cell into a malignant one. Intermediate stages have been identified and designated by terms such as "immortalization," "hyperplasia," and "preneoplastic." Tumors usually develop slowly over a long period of time. It appears that a tumor virus usually acts as a cofactor, providing only some of the steps required to generate malignant cells. Interactions of Tumor Viruses with Their Hosts Persistent Infections The known tumor viruses establish long-term persistent infections in humans. Because of differences in individual genetic susceptibilities and host immune responses, levels of virus replication and tissue tropisms may vary among persons. Host Immune Responses Viruses that establish persistent infections must avoid detection and recognition by the immune system that would eliminate the infection. Different viral evasion strategies have been identified, including :infection of sites relatively inaccessible to immune responses (human papillomavirus in the epidermis); mutation of viral antigens that allows escape from antibody and T cell recognition (human immunodeficiency virus); modulation of host major histocompatibility complex class I molecules in infected cells (adenovirus, cytomegalovirus); inhibition of antigen processing (Epstein-Barr virus); and infection and suppression of essential immune cells (human immunodeficiency virus). Mechanisms of Action by Human Cancer Viruses Tumor viruses mediate changes in cell behavior by means of a limited amount of genetic information. There are two general patterns by which this is accomplished: The tumor virus introduces a new "transforming gene" into the cell (direct-acting), or the virus alters the expression of a preexisting cellular gene or genes (indirect-acting). In either case, the cell loses control of normal regulation of growth processes. DNA repair pathways are frequently affected, leading to genetic instability and a mutagenic phenotype. Cellular transformation may be defined as a stable, heritable change in the growth control of cells in culture. No set of characteristics invariably distinguishes transformed cells from their normal. Transformation to a malignant phenotype is recognized by tumor formation when transformed cells are injected into appropriate test animals. Indirect-acting tumor viruses are not able to transform cells in culture. Cell Susceptibility to Viral Infections At the cellular level, host cells are either permissive or nonpermissive for replication of a given virus. Permissive cells support viral growth and production of progeny virus; nonpermissive cells do not. Especially with the DNA viruses, permissive cells are not transformed unless the viral replicative cycle that normally results in death of the host cell is blocked in some way; nonpermissive cells may be transformed. In contrast, a characteristic property of RNA tumor viruses is that they are not lethal for the cells in which they replicate. Cells that are permissive for one virus may be nonpermissive for another. Some viruses are associated with a single tumor type, whereas others are linked to multiple tumor types. These differences reflect the tissue tropisms of the viruses. In some viral systems, virus-transformed cells may release growth factors that affect the phenotype of neighboring uninfected cells, thereby contributing to tumor formation. It is also possible that as tumor cells collect genetic mutations during tumor growth, the need for the viral genes that drove tumor initiation may become unnecessary and will be lost from some cells. Retroviruses Retroviruses contain an RNA genome and an RNA-directed DNA polymerase (reverse transcriptase). RNA tumor viruses in this family mainly cause tumors of the reticuloendothelial and hematopoietic systems (leukemias, lymphomas) or of connective tissue (sarcomas). Important properties of the retroviruses are listed in Table 6 Table 6. Important Properties of Retroviruses. Virion: Spherical, 80–110 nm in diameter, helical nucleoprotein within icosahedral capsid Composition: RNA (2%), protein (about 60%), lipid (about 35%), carbohydrate (about 3%) Genome: Single-stranded RNA, linear, positive-sense, 7–11 kb, diploid; may be defective; may carry oncogene Proteins: Reverse transcriptase enzyme contained inside virions Envelope: Present Replication: Reverse transcriptase makes DNA copy from genomic RNA; DNA (provirus) integrates into cellular chromosome; provirus is template for viral RNA Maturation: Virions bud from plasma membrane Outstanding characteristics: Infections do not kill cells May transduce cellular oncogenes, may activate expression of cell genes Proviruses remain permanently associated with cells and are frequently not expressed Many members are tumor viruses Tumor Suppressor Genes Polyomaviruses Important properties of polyomaviruses are listed in Table 7. Table 7. Important Properties of Polyomaviruses. Virion: Icosahedral, 45 nm in diameter Composition: DNA (10%), protein (90%) Genome: Double-stranded DNA, circular, 5 kbp, MW 3 million Proteins: Three structural proteins; cellular histones condense DNA in virion Envelope: None Replication: Nucleus Outstanding characteristics: Stimulate cell DNA synthesis Viral oncoproteins interact with cellular tumor suppressor proteins Important model tumor viruses Human viruses can cause human neurologic and renal disease May cause human cancer Papillomaviruses Important properties of papillomaviruses are listed in Table 8 Table 8. Important Properties of Papillomaviruses.1 Virion: Icosahedral, 55 nm in diameter Composition: DNA (10%), protein (90%) Genome: Double-stranded DNA, circular, 8 kbp, MW 5 million Proteins: Two structural proteins; cellular histones condense DNA in virion Envelope: None Replication: Nucleus Outstanding characteristics: Stimulate cell DNA synthesis Restricted host range and tissue tropism Significant cause of human cancer, especially cervical cancer Viral oncoproteins interact with cellular tumor suppressor proteins Adenoviruses The adenoviruses comprise a large group of agents widely distributed in nature. They are medium-sized, nonenveloped viruses containing a linear genome of double-stranded DNA (26–45 kbp). Replication is speciesspecific, occurring in cells of the natural hosts. Adenoviruses commonly infect humans, causing mild acute illnesses, mainly of the respiratory and intestinal tracts. Herpesviruses These large viruses (diameter 125–200 nm) contain a linear genome of double-stranded DNA (125–240 kbp) and have a capsid with icosahedral symmetry surrounded by an outer lipid-containing envelope. Herpesviruses typically cause acute infections followed by latency and eventual recurrence in each host, including humans. In humans, herpesviruses have been linked to several specific types of tumors. Epstein-Barr (EB) herpesvirus causes acute infectious mononucleosis when it infects B lymphocytes of susceptible humans. EB virus is etiologically linked to Burkitt's lymphoma, a tumor most commonly found in children; to nasopharyngeal carcinoma (NPC), more common to posttransplant lymphomas; and to Hodgkin's disease. These tumors usually contain EB viral DNA . Kaposi's sarcoma-associated herpesvirus, also known as human herpesvirus 8 (KSHV/HHV8). It is suspected of being the cause of Kaposi's sarcoma, primary effusion lymphoma, and a particular lymphoproliferative disorder. KSHV has a number of genes that may stimulate cellular proliferation and modify host defense mechanisms. Poxviruses Poxviruses are large, brick-shaped viruses with a linear genome of double-stranded DNA (130–375 kbp). Very little is known about the nature of these proliferative diseases, but the poxvirus-encoded growth factor that is related to epidermal growth factors and to transforming growth factor may be involved. Hepatitis B Virus & Hepatitis C Virus Hepatitis B virus a member of the Hepadnaviridae family, is characterized by 42-nm spherical virions with a circular genome of double-stranded DNA (3.2 kbp). One strand of the DNA is incomplete and variable in length. In addition to causing hepatitis, hepatitis B virus is a risk factor in the development of liver cancer in humans and the development of hepatocellular carcinoma. Hepatitis C virus a member of the Flaviviridae family, contains a genome of single-stranded RNA 9.4 kb in size. It appears that the majority of infections become persistent, even in adults. Chronic infection with hepatitis C virus is also considered to be a causative factor in hepatocellular carcinoma. Most probably, hepatitis C virus acts indirectly in the development of hepatocellular carcinoma.