Human Tumor Viruses

Although many viruses were identified that caused tumors in animals, the discovery of human tumor viruses was slow and at times disappointing. Human tumor viruses simply did not follow the pattern set by experiments in animals, where tumor formation often followed viral infection rapidly and efficiently. There are several difficulties in identifying human tumor viruses. The process of viral tumorigenesis in humans is inefficient, and typically only a small percentage of infected individuals actually develop cancer. This inefficiency reflects effective immuno-surveillance by the host and possibly other factors as well. Moreover, virus infection is not sufficient for tumor formation; additional events must also occur. These events may include somatic mutation, immunosuppression, exposure to another carcinogen, or inheritance of genes that confer high susceptibility to infection or carcinogenesis. Also, viral tumorigenesis in humans is a slow process, with incubation periods measured not in days or weeks but in years or even decades. Finally, human virally induced tumors often do not produce infectious viruses. Several of these features obviously hindered epidemiological studies.

Despite these difficulties, six viruses are now widely recognized as playing an etiologic role in human cancers. Four of these viruses, human papillomaviruses (HPV), Epstein-Barr virus (EBV), hepatitis B virus (HBV), and human herpesvirus-8 (HHV-8), contain DNA genomes, and the remaining two, human T lymphotropic virus 1 (HTLV-1) and hepatitis C virus (HCV), contain RNA genomes.

1.3.1. Human Papillomaviruses

The HPVs are small, non-enveloped DNA viruses that cause benign epithelial papillomas or warts in their natural hosts, with particular HPV types causing specific types of papillomas or lesions at particular anatomic sites. The main medical importance of the HPVs is the causal role played by certain high-risk HPV types, primarily HPV16 and HPV18, in a variety of carcinomas. The most important and best documented HPV-associated cancer is cervical carcinoma (Durst et al., 1983; Bosch and Munoz, 2002), but HPV is also thought to play an etiologic role in other anogenital cancers, skin cancers in immunosuppressed individuals, and some head-and-neck tumors (e.g., Gillison, 2004).

1.3.2. Hepatitis Viruses

Hepatitis B virus and hepatitis C virus are genetically unrelated viruses. HBV is a small DNA virus that utilizes an unusual replication strategy involving an RNA intermediate (Summers and Mason, 1982), whereas HCV contains an RNA genome related to flaviviruses (Choo et al., 1989; Miller and Purcell, 1990). Infections by both viruses are prevalent in humans and can cause acute and chronic liver disease. Importantly, chronic HBV- and HCV-induced liver disease can progress to primary hepatocellular carcinoma (Beasley, 1988; Di Bisceglie, 1997).

1.3.3. Epstein-Barr Virus

Epstein-Barr virus is a herpesvirus that infects virtually all adult humans (Henle et al., 1969). Unlike the viruses mentioned above, EBV is a large, complex virus that encodes more than 100 proteins. In the developed world, EBV causes infectious mononucleosis, a benign and self-limiting proliferation of B lymphocytes, in about one-half of primarily infected adolescents or adults, while the rest and all young children undergo silent seroconversion. EBV is also believed to contribute to the origin of high incidence Burkitt's lymphoma and nasopharyngeal carcinoma, a malignant cancer of epithelial cells (Henleetal., 1969; de The et al., 1975). EBV-driven B cell lymphoproliferative disease can occur in immunosuppressed persons, such as transplant recipients (Nalesnik, 1998) andpatients with congenital immunodeficiencies such as X-linked lymphoproliferative disease (Purtilo et al., 1992). EBV also has been implicated in some forms of Hodgkin's disease and gastric carcinoma (e.g., Weiss et al., 1989).

1.3.4. Human Herpesvirus-8

HHV-8, also known as Kaposi sarcoma herpesvirus, is distantly related to EBV. This virus was first identified in the tumor DNA of a patient with Kaposi's sarcoma (Chang et al., 1994), a tumor of endothelial cells. HHV-8 is believed to play an etiologic role in this tumor, as well as in Castleman's disease and body cavity lymphoma (Sarid et al., 1999). Kaposi's sarcoma was a relatively rare tumor until the AIDS epidemic, when it became one of the most common causes of cancer death in AIDS patients (Cesarman et al., 1995). Following the introduction of highly effective antiretroviral therapy, the incidence of Kaposi sarcoma has decreased dramatically.

1.3.5. Human T Lymphotropic Virus Type I

HTLV-1 is a complex retrovirus that causes a relatively rare tumor, adult T cell leukemia/lymphoma, in the Far East and the Caribbean basin (Gallo et al., 1983), as well as some non-neoplastic diseases.

1.3.6. SV40 as a Potential Human Tumor Virus

Simian virus 40 (SV40) has also been discussed in relation to several human tumors. SV40 is a small DNA virus that causes tumors in experimental animals. The natural host of SV40 is rhesus monkeys, and there is inconclusive evidence regarding the ability of this virus to establish infections in humans. SV40 DNA has been reported to be present in some mesotheliomas, osteosarcomas, childhood brain tumors, and non-Hodgkin's B cell lymphomas and to play an etiologic role in these cancers (reviewed in Shah, 2004). However, these reports remain controversial.

1.3.7. Viral Tumors in the Developing World

In summary, more than 10% of all cancers in humans is strongly associated with infection by tumor viruses (Table 1.1) (Parkin et al., 1999). In addition, HIV infection and its associated immunosuppression predisposes individuals to cancer development. The great majority of tumors associated with virus infection occur in the developing world, where they are a leading cause of cancer death. The preponderance of such tumors in the developing world is due to several factors.

Table 1.1. Annual Number of Viral-Associated Cases Worldwide*

Agent

Cancer

No. of cases

Human papillomaviruses

Cervical cancer

492,800

Anogenital carcinoma

46, 700

Oral and pharyngeal carcinoma

14,500

Hepatitis B viruses

Hepatocellular carcinoma

535,640

Hepatitis C viruses

Kaposi's sarcoma herpes virus

Kaposi's sarcoma

66, 000

Epstein-Barr virus

Nasopharyngeal carcinoma

78, 100

Hodgkin's disease

28, 600

Burkitt's lymphoma

6, 700

Human T lymphotropic virus

Adult T cell leukemia/lymphoma

3, 000

* Compiled by D.M. Parkin from 2000 statistics.

* Compiled by D.M. Parkin from 2000 statistics.

In some cases, infection by the tumor virus is more prevalent in the developing world. For example, there is a high correlation between the areas of the world with a high prevalence of chronic HBV infection and hepatocellular carcinoma (Beasley, 1988). In addition, ineffective screening programs to identify lesions at a precancerous, treatable stage may contribute to the high incidence of virally associated cancer in the developing world. The introduction of effective Pap smear screening programs for cervical precursor lesions caused a dramatic drop in the incidence of cervical cancer in the developed world (Gustafsson et al., 1997). Poor nutrition and general health status resulting in impaired immune function and other social, behavioral, and possibly genetic factors may also contribute to the high prevalence of virally associated tumors in the developing world.

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