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Herpes Simplex Virus Type 2 and Human PapillomavirusesAllan Hildesheim, Ph.D.*
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Since the carcinogenic potential of viruses was first recognized by Rous in 1911, numerous additional viruses have been shown or hypothesized to be linked to the development of various cancers in humans (Evans et al., 1990; Rawls et al., 1977; Reeves et al., 1989b). Herpes simplex virus type 2 (HSV-2) is one such virus. HSV-2 belongs to the herpes family of viruses, which also includes HSV-1, a virus known to infect the oral mucosa and to result in canker sores. HSV-2 is a sexually transmitted virus that has a predilection for infecting male and female genitalia, although it has also been shown to infect the oral mucosa (Corey et al., 1986b). An important feature of HSV-2 is its ability to become latent and to persist in the host for many years after infection (Corey et al., 1986a). HSV-2 infection can be either symptomatic or asymptomatic. The frequency of infections that result in symptoms is unknown. However, serologic studies that have measured the prevalence of HSV-2 antibodies in different populations indicate that a sizable proportion of infections with this virus are likely to be asymptomatic. Given the fact that these asymptomatic infections do not come to the attention of the medical community, it has been difficult to determine the overall prevalence of this virus. Nonetheless, one study that examined HSV-2 antibody levels among participants of the National Health and Nutrition Examination Survey reported an overall prevalence of 16.4 percent (Johnson et al., 1989). This indicates that nearly one in five individuals in the population may be carriers of the HSV-2 virus, with the figure being even higher in certain segments of the population. In the late 1960s and 1970s, several studies indicated that women exposed to HSV-2 were at two- to four-fold elevated risks of developing cervical cancer (Kaufman et al., 1986). Laboratory evidence supported this hypothesis; in-vitro and in-vivo studies demonstrated the transforming ability of HSV-2 as well as its potential carcinogenic effects (Wentz et al., 1983). However, more recent evidence suggests that, while HSV-2 might be involved in the development of cervical cancer, it is not likely to play as important a role as was once believed. Evidence now points to human papilloma viruses (HPV) as the viruses that are likely to play a central role in the development of this disease (Reeves et al., 1989b; Koutsky et al., 1988). HPV comprises a family of viruses that includes upwards of 60 viral types. These viruses are known to be the cause of warts at various sites. About 20 types have been shown to infect the genital area (Koutsky et al., 1988). In addition, various HPV types are known to infect the skin, oral cavity, larynx, and anus. As is the case of HSV-2, a large proportion of HPV infections are asymptomatic and may therefore go undetected. This has made it difficult to determine the prevalence of this virus in the general population; most estimates range from 10 to 40 percent, depending on the population studied, the method used to detect the virus, and the viral types detected (Koutsky et al., 1988). The association between HPV and cervical cancer was first suggested by Harold zur Hausen in 1974 (zur Hausen, 1974). Since that time, numerous epidemiologic and laboratory studies have supported an association between HPV and cervical cancer (Reeves et al., 1989b; Koutsky et al., 1988). It has been demonstrated that women who are infected with HPV are at higher risk of developing cervical intraepithelial neoplasia (a benign precursor of cervical cancer) as well as cervical cancer. It is estimated, from case-control studies, that women infected with HPV are 10 or more times more likely to develop cervical cancer than women who are HPV-negative (Koutsky et al., 1988; Reeves et al., 1989a). In vitro laboratory studies have been able to isolate those fragments of the HPV DNA that are likely to be responsible for its ability to transform cells in humans, and HPV DNA fragments have been detected in tumor samples obtained from cervical cancer patients. Given the high prevalence of HPV infection relative to the incidence of cervical cancer, it is believed that HPV alone is not capable of inducing cervical cancer and that exposure to other factors, called cofactors, must be important determinants of which HPV infected women will develop the disease. Numerous exposures are currently under investigation as possible cofactors. These include host factors such as immunological status, including infection with HIV, as well as environmental exposures such as smoking, oral contraceptive use, diet, parity, and other sexually transmitted diseases, including HSV-2. HSV-2 and HPV are also believed to be associated with the development of other cancers. However, less is known about the link between these viruses and cancers of other sites. Limited evidence suggests that HSV-2 might be involved in the etiology of other genital cancers (Kaufman et al., 1981). HPV has been linked to numerous cancers, including other genital tumors, as well as skin, oral, laryngeal, and anal cancers, but causation is less firmly established. |
* From the Environmental Epidemiology Branch, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland
