Oncovirus

An oncovirus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, often called oncornaviruses to denote their RNA virus origin.^[1] 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.

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.^[2] These cancers might be easily prevented through vaccination (e.g., papillomavirus vaccines), diagnosed with simple blood tests, and treated with less-toxic antiviral compounds.

Background

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 are 19th-century constructs developed by Robert Koch to establish the likelihood that Bacillus anthracis will cause anthrax disease and 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.^[3] 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,^[4] 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 (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.

A direct oncogenic viral mechanism^[5] involves either insertion of additional viral oncogenic genes into the host cell or to enhance already existing oncogenic genes (proto-oncogenes) in the genome. 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.

Timeline of discovery

• 1908: Vilhelm Ellerman and Olaf Bang, University of Copenhagen, first demonstrated that avian sarcoma leukosis virus could be transmitted after cell-free filtration to new chickens, causing leukemia.^[6]
• 1910: Peyton Rous at Rockefeller extended Bang and Ellerman's experiments to show filtrable cell-free transmission of a solid tumor sarcoma to chickens (now known as Rous sarcoma). The reasons why chickens are so receptive to such transmission may involve unusual characteristics of stability or instability as they relate to endogenous retroviruses.^[7][8]
• 1933: Richard Edwin Shope discovered cottontail rabbit papillomavirus or Shope papillomavirus, the first mammalian tumor virus.
• 1936: Mouse mammary tumor virus shown by John J. Bittner to be an "extrachromosomal factor" (i.e., virus) transmitted among laboratory strains of mice by breast feeding.^[9] This was an extension of work on murine breast cancer caused by a transmissible agent as early as 1915, by A.F. Lathrop and L. Loeb.^[10]
• 1954-9: Ludwik Gross, working at the Bronx VA medical center isolated murine polyomavirus, which caused a variety of salivary gland and other tumors in specific strains of newborn mice, subsequently confirmed by Sarah Stewart and Bernice Eddy.
• 1961: Simian Vacuolating virus 40 (SV40) discovered by Eddy at NIH, and Hillman and Sweet at Merck laboratory as a rhesus macaque virus contaminating cells used to make of Salk and Sabin polio vaccines. Several years later it was shown to cause cancer in Syrian hamsters, raising concern about possible human health implications. Scientific consensus now strongly agrees that this is not likely to cause human cancer.^[11][12]

Human oncoviruses

• 1964: Anthony Epstein, Bert Achong and Yvonne Barr identify the first human oncovirus from Burkitt lymphoma cells. A herpesvirus, this virus is formally known as human herpesvirus 4 but more commonly called Epstein-Barr Virus or EBV.^[13]
• mid-1960s: Baruch Blumberg first physically isolated and characterized Hepatitis B while at NIH and later Fox Chase Laboratory, receiving the 1976 Nobel Prize in Medicine or Physiology.^[14] 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.^[15]
• 1980: Human T-lymphotropic virus 1 (HTLV I), the first human retrovirus was discovered by Bernard Poiesz and Robert Gallo^[16][17] at NIH and Mistuaki Yoshida and coworkers in Japan.^[18]
• 1984–86: Harald zur Hausen, together with Lutz Gissman, discovered first HPV16 and then HPV18 responsible for approximately 70% of cervical cancers. For discovery that human papillomaviruses (HPV) cause human cancer, zur Hausen won a 2008 Nobel Prize.^[19]
• 1987: Hepatitis C virus, or HCV, discovered by panning a cDNA library made from diseased tissues for foreign antigens recognized with patient sera. This work was performed by Michael Houghton at Chiron, a biotechnology company, and D.W. Bradley at CDC.^[20] Controversy erupted when Chiron claimed all rights to the discovery although the work had been performed under contract with the CDC using Bradley's materials and ideas. Eventually, this was amicably settled. HCV was subsequently shown to be a major contributor to liver cancer (hepatocellular carcinoma) worldwide.
• 1994: Patrick S. Moore and Yuan Chang (a husband and wife team^[21] then at Columbia University) working together with Frank Lee and Ethel Cesarman^[22] isolated Kaposi sarcoma-associated herpesvirus (KSHV or HHV8) using representational difference analysis. This search was prompted from work by V. Beral, T. Peterman and H. Jaffe who showed from accumulating evidence from the epidemic of Kaposi sarcoma associated with AIDS, that this cancer must have another infectious cause besides HIV itself.^[23] This agent was predicted to be a new virus. Subsequent studies revealed that KSHV is indeed the "KS agent" and is responsible for the epidemiologic patterns of KS and related cancers.^[24]
• 2008: Chang and Moore, now at the University of Pittsburgh Cancer Institute, developed a new method to identify cancer viruses based on computer subtraction of human sequences from a tumor transcriptome, called digital transcriptome subtraction (DTS).^[25] 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.^[26] This is the first polyomavirus to be well-established as the cause for a human cancer.

History

The theory that cancer could be caused by a virus began with the experiments of Oluf Bang and Vilhelm Ellerman in 1908 who first show that avian erythroblastosis (a form of chicken leukemia) could be transmitted by cell-free extracts.^[27] This was subsequently confirmed for solid tumors in chickens in 1910-1911 by Peyton Rous.^[28][29]

By the early 1950s it was known that viruses could remove and incorporate genes and genetic material in cells. It was suggested that these new genes inserted into cells could make the cell cancerous. Many of these viral oncogenes have been discovered and identified to cause cancer.

The main viruses associated with human cancers are human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, human T-lymphotropic virus, Kaposi's sarcoma-associated herpesvirus(KSHV) and Merkel cell polyomavirus. Experimental and epidemiological data imply a causative role for viruses and they appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage.^[30] The mode of virally induced tumors can be divided into two, acutely transforming or slowly transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral 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.

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.

Advances in cancer research have made a vaccines designed to prevent cancer. The hepatitis B vaccine is the first vaccine that has been established to prevent cancer (hepatocellular carcinoma) by preventing infection with the causative virus. In 2006, the U.S. Food and Drug Administration approved a 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.

Small DNA tumor viruses

Small DNA tumor viruses are a group of double-stranded DNA viruses, made up of the polyomavirus, the adenovirus and the papillomavirus families. The causal link between papillomaviruses and some human cancers is well known and a role for polyomavirus in human cancer has recently been established.^[31] Adenoviruses do not cause cancer in humans but these viruses have been exploited as delivery vehicles in gene therapy for diseases such as cystic fibrosis and cancer.^[31]

Mechanism

Brief history

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

DNA viruses

• Human papilloma virus (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.^[32] Some types of HPV increase the risk of, e.g., cervical cancer.
• Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is associated with Kaposi’s sarcoma, a type of skin cancer.^[33]
• Epstein-Barr virus (EBV or HHV-4) is associated with four types of cancers
• Merkel cell polyomavirus – a polyoma virus – is associated with the development of Merkel cell carcinoma^[26]
• Human cytomegalovirus (CMV or HHV-5) is associated with mucoepidermoid carcinoma and possibly other malignancies.^[34]

RNA viruses

Not all oncoviruses are DNA viruses. Some RNA viruses have also been associated such as the hepatitis C virus as well as certain retroviruses, e.g., human T-lymphotropic virus (HTLV-1) and Rous sarcoma virus (RSV).

Overview table

Virus	Percent of cancers[2]	Associated cancer types
Hepatitis B (HBV)		Hepatocarcinoma[35][36]
Hepatitis C (HCV)		The type 1b is associated with hepatocarcinoma[35][36]
Human T-lymphotropic virus (HTLV)	0.03	Adult T-cell leukemia[37]
Human papillomaviruses (HPV)	5.2	The types 16 and 18 are associated with cancers of cervix,[38] anus,[38] penis,[38] vulva/vagina,[2] and oropharyngeal cancer.[2]
Kaposi’s sarcoma-associated herpesvirus (HHV-8)	0.9	Kaposi’s sarcoma, multicentric Castleman's disease and primary effusion lymphoma
Merkel cell polyomavirus (MCV)	NA	Merkel cell carcinoma
Epstein–Barr virus (EBV)	NA	Burkitt’s lymphoma, Hodgkin’s lymphoma, Post-transplant lymphoproliferative disease and Nasopharyngeal carcinoma.[39]

Estimated percent of new cancers attributable to the virus worldwide in 2002.^[2] NA indicates not available. The association of other viruses with human cancer is continually under research.

See also

• Carcinogen
• Oncogenic
• Oncogene
• Adult T-cell leukemia/lymphoma
• Cancer bacteria
• Oncolytic virus, a virus that infects and kills cancer cells
• Gag-onc fusion protein
• List of infectious diseases

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External links

• Oncoviruses at the US National Library of Medicine Medical Subject Headings (MeSH)