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.
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, 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 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.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, can cause cancers, as can retroviruses having both DNA and RNA genomes. 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. 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
A direct oncogenic viral mechanism involves either insertion of additional viral oncogenic genes into the host cell or to enhance already existing oncogenic genes 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. Acquiring or enhancing oncogenecity can be evolutionarily favorable to the virus because increasing cell proliferation tends to also increase viral load.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 from a mature tumor that has accumulated sufficient mutations and growth conditions 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
DNA oncoviruses typically impair two families of tumor suppressor proteins: tumor proteins p53 and the retinoblastoma proteins. 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, 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 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, 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 prevents p53 from regulating genes by binding to the site on p53 which binds to the genome. In SV40, the large T antigen 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, 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, forming a complex which causes the rapid and specific ubiquitination of p53.Inactivation of Rb
Rb is inactivated by different but analogous viral oncoproteins. The adenovirus early region 1A 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.
Oncogenic retroviruses
Retroviruses have historically played an important role in identifying cellular oncogenes. In many cases, a retrovirus was first observed to induce malignant transformation in infected cells. Work was then done to find the part of the virus genome responsible, isolating the viral oncogene. It was then discovered that this viral oncogene has homologs in the cellular genome, suggesting that the cellular version may also cause cancer when mutated: a prediction that has turned out true in the case of Src, Kras, Hras, and many other proteins.Based on sequence comparison, it was deduced that in all cases, the retrovirus had picked up the gene from the cellular genome rather than the other way around. This kind of acquisition happens more commonly in retroviruses than in other types of viruses because the retrovirus life-cycles includes integrating the reversed-transcribed version of the viral genome into a host chromosome, followed by it being transcribed out to form the progeny virion genome later. An interruption in the reverse-transcription process can cause a partial viral genome to be inserted into the host chromosome upstream of a gene, leading to the transcription of a malformed progeny virion RNA that starts with viral sequences but ends with host sequences. When this malformed RNA is packaged with correct RNA into a new viron, a new generation of reverse transcription would see the DNA products of these two strands cross-over and recombine into a new strand, a version of the genome with a cellular insertion.
All replication-capable retroviruses have three major coding domains; gag, pol and env. In the gag region of the virus, the synthesis of the structural 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. Env encodes the viral envelope protein, essential for cell entry. Some oncoviruses such as the Simian sarcoma virus are replication-defective because the insertion coincided with the deletion of one of these coding domains, rendering them dependent on a closely-related virus for replication.