Oncovirus

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(Redirected from
DNA tumour virus
)

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.[1][2][3]

An oncovirus or oncogenic virus is a virus that can cause cancer.[4] This term originated from studies of acutely transforming retroviruses in the 1950–60s,[5] when the term "oncornaviruses" was used to denote their RNA virus origin.[6] 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.[7] A 2020 study of 2,658 samples from 38 different types of cancer found that 16% were associated with a virus.[8] 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.[9] 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,[10]
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

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.[citation needed
]

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

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.[12]

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.[citation needed]

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.[citation needed]

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.[13] 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.[14]

While several DNA oncoviruses have been discovered, three have been studied extensively.

human papillomavirus-16 (HPV-16) has been shown to lead to cervical cancer and other cancers, including head and neck cancer.[17] 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.[citation needed
]

Integration of viral DNA

DNA oncoviruses transform infected cells by integrating their DNA into the host cell's genome.[18] The DNA is believed to be inserted during transcription or replication, when the two annealed strands are separated.[18] This event is relatively rare and generally unpredictable; there seems to be no deterministic predictor of the site of integration.[18] After integration, the host's cell cycle loses regulation from Rb and p53, and the cell begins cloning to form a tumor.[19]

G1/S Checkpoint

Rb and p53 regulate the transition between

Cdk2 complex, which inhibits Rb, forming a positive feedback loop, keeping the cell in G1 until the input crosses a threshold.[20] 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.[citation needed
]

Inactivation of p53

Viruses employ various methods of inactivating p53. The

ubiquitination of p53.[23]

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.[13] SV40 uses the same protein for inactivating Rb, LT, to inactivate p53.[21] HPV contains a protein, E7, which can bind to Rb in much the same way.[24] 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.[22]

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.[13]

SV40 has been well studied and does not cause cancer in humans, but a recently discovered analogue called

Merkel cell carcinoma, a form of skin cancer.[25] The Rb binding feature is believed to be the same between the two viruses.[25]

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 shown 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 integrase. 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

RNA viruses

Not all oncoviruses are

human T-lymphotropic virus (HTLV-1) and Rous sarcoma virus
(RSV).

Overview table

Virus Percent of cancers[7] Associated cancer types
Hepatitis B virus (HBV)
Hepatocarcinoma[33]
Hepatitis C virus (HCV) HCV is a known carcinogen, causing
hepatocarcinoma[36]
Human T-lymphotropic virus
(HTLV)		 0.03
Adult T-cell leukemia[37]
Human papillomaviruses
(HPV)		 5.2 HPV types 16 and 18 are associated with cancers of cervix,[7][27][28][30][31] anus,[7][29][30] penis,[7][29][30] vulva,[7][29][30] vagina,[7][29][30] and HPV-positive oropharyngeal cancers.[7][29][32] According to statistics in the United States, females are more impacted by HPV-associated cancers (83%) than males (74%).[38]
Kaposi's sarcoma-associated herpesvirus (HHV-8) 0.9
Castleman's disease and primary effusion lymphoma
Merkel cell polyomavirus (MCV) NA
Merkel cell carcinoma
Epstein–Barr virus (EBV) NA
post-transplant lymphoproliferative disease, nasopharyngeal carcinoma[39] and a subtype of stomach cancer.[40]

Estimated percent of new cancers attributable to the virus worldwide in 2002.[7] NA indicates not available. The association of other viruses with human cancer is continually under research.

Main viruses associated with human cancer

Major capsid protein L1 pentamer, Human papillomavirus 11
The structure of the hepatitis B virus

The main viruses associated with human cancers are the

promoter or other transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly transforming viruses have very long tumor latency compared to acutely transforming viruses, which already carry the viral oncogene.[citation needed
]

Hepatitis viruses, including hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer in 0.47% of hepatitis B patients per year (especially in Asia, less so in North America), and in 1.4% of hepatitis C carriers per year. Liver cirrhosis, whether from chronic viral hepatitis infection or alcoholism, is associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Worldwide, liver cancer is one of the most common, and most deadly, cancers due to a huge burden of viral hepatitis transmission and disease.[citation needed]

Through advances in cancer research, vaccines designed to prevent cancer have been created. The hepatitis B vaccine is the first vaccine that has been established to prevent cancer (

human papilloma virus vaccine, called Gardasil. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts. In March 2007, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) officially recommended that females aged 11–12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization.[citation needed
]

History

The history of cancer virus discovery is intertwined with the

nematode worm could provoke stomach cancer in rats. But it was not recognized that cancer could have infectious origins until much later as virus had first been discovered by Dmitri Ivanovsky and Martinus Beijerinck at the close of the 19th century.[42]

History of non-human oncoviruses

Rabbit with Shope papilloma virus infection.

The theory that cancer could be caused by a virus began with the experiments of

liquid tumor in mice by .[48] In 1933 Richard Shope and Edward Weston Hurst showed that warts from wild cottontail rabbits contained the Shope papilloma virus.[42] In 1936 John Joseph Bittner identified the mouse mammary tumor virus, an "extrachromosomal factor" (i.e. virus) that could be transmitted between laboratory strains of mice by breast feeding.[49]

By the early 1950s, it was known that viruses could remove and incorporate genes and genetic material in cells. It was suggested that such types of viruses could cause cancer by introducing new genes into the genome. Genetic analysis of mice infected with

tumors in mice.[51] This compound was subsequently identified as a virus by Sarah Stewart and Bernice Eddy at the National Cancer Institute, after whom it was once called "SE polyoma".[52][53][54] In 1957 Charlotte Friend discovered the Friend virus, a strain of murine leukemia virus capable of causing cancers in immunocompetent mice.[48] Though her findings received significant backlash, they were eventually accepted by the field and cemented the validity of viral oncogenesis.[55]

In 1961 Eddy discovered the simian vacuolating virus 40 (

Syrian hamsters, raising concern about possible human health implications. Scientific consensus now strongly agrees that this is not likely to cause human cancer.[56][57]

History of human oncoviruses

In 1964

National Institute of Health (NIH) and later the Fox Chase Cancer Center.[59] Although this agent was the clear cause of hepatitis and might contribute to liver cancer hepatocellular carcinoma, this link was not firmly established until epidemiologic studies were performed in the 1980s by R. Palmer Beasley and others.[60]

In 1980 the first human retrovirus, Human T-lymphotropic virus 1 (HTLV-I), was discovered by Bernard Poiesz and Robert Gallo at NIH,[61][62] and independently by Mitsuaki Yoshida and coworkers in Japan.[63] But it was not certain whether HTLV-I promoted leukemia. In 1981 Yorio Hinuma and his colleagues at Kyoto University reported visualization of retroviral particles produced by a leukemia cell line derived from patients with Adult T-cell leukemia/lymphoma. This virus turned out to be HTLV-1 and the research established the causal role of the HTLV-1 virus to ATL.[42]

Michael Houghton and Charles M. Rice
leading to the discovery of HCV as the causative agent of non-A, non-B hepatitis.

Between 1984 and 1986

Michael Houghton at Chiron, a biotechnology company, and Daniel W. Bradley at the Centers for Disease Control and Prevention (CDC).[65] HCV was subsequently shown to be a major contributor to Hepatocellular carcinoma (liver cancer) worldwide.[42]

In 1994 Patrick S. Moore and Yuan Chang at Columbia University), working together with Ethel Cesarman,[66][67] isolated Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) using representational difference analysis. This search was prompted by work from Valerie Beral and colleagues who inferred from the epidemic of Kaposi's sarcoma among patients with AIDS that this cancer must be caused by another infectious agent besides HIV, and that this was likely to be a second virus.[68] Subsequent studies revealed that KSHV is the "KS agent" and is responsible for the epidemiologic patterns of KS and related cancers.[69]

In 2008 Yuan Chang and Patrick S. Moore developed a new method to identify cancer viruses based on computer subtraction of human sequences from a tumor transcriptome, called digital transcriptome subtraction (DTS).[70] DTS was used to isolate DNA fragments of Merkel cell polyomavirus from a Merkel cell carcinoma and it is now believed that this virus causes 70–80% of these cancers.[25]

See also

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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Oncovirus&oldid=1211052974#DNA_viruses"