oncovirus oncovirus an oncovirus or oncogenic virus is a virus that can cause cancer. this term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term "oncornaviruses" was used to denote their rna virus origin. with the letters "rna" removed, it now refers to any virus with a dna or rna genome causing cancer and is synonymous with "tumor virus" or "cancer virus". the vast majority of human and animal viruses do not cause cancer, probably because of longstanding co-evolution between the virus and its host. oncoviruses have been important not only in epidemiology, but also in investigations of cell cycle control mechanisms such as the retinoblastoma protein. percentage of people infected with hepatitis c in 2015. the hepatitis c virus is the cause of hepatitis c and some cancers such as liver cancer (hepatocellular carcinoma, abbreviated hcc) and lymphomas in humans. the world health organization's international agency for research on cancer estimated that in 2002, infection caused 17.8% of human cancers, with 11.9% caused by one of seven viruses. a 2020 study of 2,658 samples from 38 different types of cancer found that 16% were associated with a virus. these cancers might be easily prevented through vaccination (e.g., papillomavirus vaccines), diagnosed with simple blood tests, and treated with less-toxic antiviral compounds. causality generally, tumor viruses cause little or no disease after infection in their hosts, or cause non-neoplastic diseases such as acute hepatitis for hepatitis b virus or mononucleosis for epstein–barr virus. a minority of persons (or animals) will go on to develop cancers after infection. this has complicated efforts to determine whether or not a given virus causes cancer. the well-known koch's postulates, 19th-century constructs developed by robert koch to establish the likelihood that bacillus anthracis will cause anthrax disease, are not applicable to viral diseases. firstly, this is because viruses cannot truly be isolated in pure culture—even stringent isolation techniques cannot exclude undetected contaminating viruses with similar density characteristics, and viruses must be grown on cells. secondly, asymptomatic virus infection and carriage is the norm for most tumor viruses, which violates koch's third principle. relman and fredericks have described the difficulties in applying koch's postulates to virus-induced cancers. finally, the host restriction for human viruses makes it unethical to experimentally transmit a suspected cancer virus. other measures, such as a. b. hill's criteria, are more relevant to cancer virology but also have some limitations in determining causality. simplified diagram of the structure of the epstein–barr virus (ebv). tumor viruses come in a variety of forms: viruses with a dna genome, such as adenovirus, and viruses with an rna genome, like the hepatitis c virus (hcv), can cause cancers, as can retroviruses having both dna and rna genomes (human t-lymphotropic virus and hepatitis b virus, which normally replicates as a mixed double and single-stranded dna virus but also has a retroviral replication component). in many cases, tumor viruses do not cause cancer in their native hosts but only in dead-end species. for example, adenoviruses do not cause cancer in humans but are instead responsible for colds, conjunctivitis and other acute illnesses. they only become tumorigenic when infected into certain rodent species, such as syrian hamsters. some viruses are tumorigenic when they infect a cell and persist as circular episomes or plasmids, replicating separately from host cell dna (epstein–barr virus and kaposi's sarcoma-associated herpesvirus). other viruses are only carcinogenic when they integrate into the host cell genome as part of a biological accident, such as polyomaviruses and papillomaviruses. oncogenic viral mechanism illustration of how a normal cell is converted to a cancer cell, when an oncogene becomes activated. a direct oncogenic viral mechanism involves either insertion of additional viral oncogenic genes into the host cell or to enhance already existing oncogenic genes (proto-oncogenes) in the genome. for example, it has been shown that vflip and vcyclin interfere with the tgf-β signaling pathway indirectly by inducing oncogenic host mir17-92 cluster. indirect viral oncogenicity involves chronic nonspecific inflammation occurring over decades of infection, as is the case for hcv-induced liver cancer. these two mechanisms differ in their biology and epidemiology: direct tumor viruses must have at least one virus copy in every tumor cell expressing at least one protein or rna that is causing the cell to become cancerous. because foreign virus antigens are expressed in these tumors, persons who are immunosuppressed such as aids or transplant patients are at higher risk for these types of cancers. chronic indirect tumor viruses, on the other hand, can be lost (at least theoretically) from a mature tumor that has accumulated sufficient mutations and growth conditions (hyperplasia) from the chronic inflammation of viral infection. in this latter case, it is controversial but at least theoretically possible that an indirect tumor virus could undergo "hit-and-run" and so the virus would be lost from the clinically diagnosed tumor. in practical terms, this is an uncommon occurrence if it does occur. dna oncoviruses a micrograph showing cells with abnormal p53 expression (brown) in a brain tumor. dna oncoviruses typically impair two families of tumor suppressor proteins: tumor proteins p53 and the retinoblastoma proteins (rb). it is evolutionarily advantageous for viruses to inactivate p53 because p53 can trigger cell cycle arrest or apoptosis in infected cells when the virus attempts to replicate its dna. similarly, rb proteins regulate many essential cell functions, including but not limited to a crucial cell cycle checkpoint, making them a target for viruses attempting to interrupt regular cell function. while several dna oncoviruses have been discovered, three have been studied extensively. adenoviruses can lead to tumors in rodent models but do not cause cancer in humans; however, they have been exploited as delivery vehicles in gene therapy for diseases such as cystic fibrosis and cancer. simian virus 40 (sv40), a polyomavirus, can cause tumors in rodent models but is not oncogenic in humans. this phenomenon has been one of the major controversies of oncogenesis in the 20th century because an estimated 100 million people were inadvertently exposed to sv40 through polio vaccines. the human papillomavirus-16 (hpv-16) has been shown to lead to cervical cancer and other cancers, including head and neck cancer. these three viruses have parallel mechanisms of action, forming an archetype for dna oncoviruses. all three of these dna oncoviruses are able to integrate their dna into the host cell, and use this to transcribe it and transform cells by bypassing the g1/s checkpoint of the cell cycle. integration of viral dna dna oncoviruses transform infected cells by integrating their dna into the host cell's genome. the dna is believed to be inserted during transcription or replication, when the two annealed strands are separated. this event is relatively rare and generally unpredictable; there seems to be no deterministic predictor of the site of integration. after integration, the host's cell cycle loses regulation from rb and p53, and the cell begins cloning to form a tumor. g1/s checkpoint rb and p53 regulate the transition between g1 and s phase, arresting the cell cycle before dna replication until the appropriate checkpoint inputs, such as dna damage repair, are completed. p53 regulates the p21 gene, which produces a protein which binds to the cyclin d-cdk4/6 complex. this prevents rb phosphorylation and prevents the cell from entering s phase. in mammals, when rb is active (unphosphorylated), it inhibits the e2f family of transcription factors, which regulate the cyclin e-cdk2 complex, which inhibits rb, forming a positive feedback loop, keeping the cell in g1 until the input crosses a threshold. to drive the cell into s phase prematurely, the viruses must inactivate p53, which plays a central role in the g1/s checkpoint, as well as rb, which, though downstream of it, is typically kept active by a positive feedback loop. inactivation of p53 viruses employ various methods of inactivating p53. the adenovirus e1b protein (55k) prevents p53 from regulating genes by binding to the site on p53 which binds to the genome. in sv40, the large t antigen (lt) is an analogue; lt also binds to several other cellular proteins, such as p107 and p130, on the same residues. lt binds to p53's binding domain on the dna (rather than on the protein), again preventing p53 from appropriately regulating genes. hpv instead degrades p53: the hpv protein e6 binds to a cellular protein called the e6-associated protein (e6-ap, also known as ube3a), forming a complex which causes the rapid and specific ubiquitination of p53. inactivation of rb rb is inactivated (thereby allowing the g1/s transition to progress unimpeded) by different but analogous viral oncoproteins. the adenovirus early region 1a (e1a) is an oncoprotein which binds to rb and can stimulate transcription and transform cells. sv40 uses the same protein for inactivating rb, lt, to inactivate p53. hpv contains a protein, e7, which can bind to rb in much the same way. rb can be inactivated by phosphorylation, or by being bound to a viral oncoprotein, or by mutations—mutations which prevent oncoprotein binding are also associated with cancer. variations dna oncoviruses typically cause cancer by inactivating p53 and rb, thereby allowing unregulated cell division and creating tumors. there may be many different mechanisms which have evolved separately; in addition to those described above, for example, the human papillomavirus inactivates p53 by sequestering it in the cytoplasm. sv40 has been well studied and does not cause cancer in humans, but a recently discovered analogue called merkel cell polyomavirus has been associated with merkel cell carcinoma, a form of skin cancer. the rb binding feature is believed to be the same between the two viruses. rna oncoviruses in the 1960s, the replication process of rna virus was believed to be similar to other single-stranded rna. single-stranded rna replication involves rna-dependent rna synthesis which meant that virus-coding enzymes would make partial double-stranded rna. this belief was proven to be incorrect because there were no double-stranded rna found in the retrovirus cell. in 1964, howard temin proposed a provirus hypothesis, but shortly after reverse transcription in the retrovirus genome was discovered. description of virus all retroviruses have three major coding domains; gag, pol and env. in the gag region of the virus, the synthesis of the internal virion proteins are maintained which make up the matrix, capsid and nucleocapsid proteins. in pol, the information for the reverse transcription and integration enzymes are stored. in env, it is derived from the surface and transmembrane for the viral envelope protein. there is a fourth coding domain which is smaller, but exists in all retroviruses. pol is the domain that encodes the virion protease. retrovirus enters host cell the retrovirus begins the journey into a host cell by attaching a surface glycoprotein to the cell's plasma membrane receptor. once inside the cell, the retrovirus goes through reverse transcription in the cytoplasm and generates a double-stranded dna copy of the rna genome. reverse transcription also produces identical structures known as long terminal repeats (ltrs). long terminal repeats are at the ends of the dna strands and regulates viral gene expression. the viral dna is then translocated into the nucleus where one strand of the retroviral genome is put into the chromosomal dna by the help of the virion intergrase. at this point the retrovirus is referred to as provirus. once in the chromosomal dna, the provirus is transcribed by the cellular rna polymerase ii. the transcription leads to the splicing and full-length mrnas and full-length progeny virion rna. the virion protein and progeny rna assemble in the cytoplasm and leave the cell, whereas the other copies send translated viral messages in the cytoplasm. classification kaposi's sarcoma is a cancer that can form masses in the skin and is caused by the kaposi's sarcoma-associated herpesvirus (kshv), also called hhv-8. dna viruses human papillomavirus (hpv), a dna virus, causes transformation in cells through interfering with tumor suppressor proteins such as p53. interfering with the action of p53 allows a cell infected with the virus to move into a different stage of the cell cycle, enabling the virus genome to be replicated. forcing the cell into the s phase of the cell cycle could cause the cell to become transformed. human papillomavirus infection is a major cause of cervical cancer, vulvar cancer, vaginal cancer, penis cancer, anal cancer, and hpv-positive oropharyngeal cancers. there are nearly 200 distinct human papillomaviruses (hpvs), and many hpv