Papillomaviruses (PV) have been linked to widespread, serious human diseases, especially carcinomas of the genital and oral mucosa. It is estimated that there are currently somewhere in the neighborhood of tens of millions of women who suffer from human papilloma virus (HPV) infection of the genital tract. Many of these women eventually develop cancer of the cervix. For example, it has been estimated that about twenty percent (20%) of all cancer deaths in women worldwide are from cancers which are associated with HPV. It has also been estimated that 90% of all cervical cancer is linked to HPV.
Papillomaviruses induce benign, dysplastic and malignant hyperproliferations of skin or mucosal epithelium (see, for example, Mansur and Androphy, (1993) Biochim Biophys Acta 1155:323-345; Pfister (1984) Rev. Physiol. Biochem. Pharmacol. 99:111-181; and Broker et al. (1986) Cancer Cells 4:17-36, for reviews of the molecular, cellular, and clinical aspects of the papillomaviruses). Almost 70 human papillomavirus types have been identified, and different papillomavirus types are known to cause distinct diseases, Pfister, (1987) Adv. Cancer Res., 48:113-147, Syrjanen, (1984) Obstet. Gynecol. Survey 39:252-265. Human papillomaviruses (HPVs) are a heterogeneous group of DNA tumor viruses associated with hyperplastic (warts, condylomata), pre-malignant and malignant lesions (carcinomas) of squamous epithelium. For example, HPV types 1 and 2 cause common warts, and types 6 and 11 cause warts of the external genitalia, anus and cervix. HPV, types 16, 18, 31 and 33 have been isolated from the majority of cervical cancers with HPV-16 present in about 50 percent of all cervical cancers. These HPV's are referred to as "high risk". While HPV 6 and 11 are the most common isolates for cervical warts, these infections rarely progress to invasive cancer, and therefore these HPV's are referred to as "low risk".
Studies of viral gene expression in carcinomas suggest the importance of two HPV encoded proteins, E6 and E7, in malignant development and these proteins have been shown to encode transforming and immortalizing activities. The two proteins show some functional resemblance to the transforming proteins of other small DNA tumor viruses such as adenovirus and SV40. E7 shares functional and structural features with the adenovirus E1A proteins. Like Ad E1A and the large T proteins of the polyomaviruses, E7 can complex pRB. Likewise, the E6 oncoprotein encoded by the "high risk" HPV's can form a complex with p53. In vitro, E6 promotes the degradation of p53 and this degradation involves the ubiquitin-dependent protease system. The selective degradation of cellular negative regulatory proteins such as p53 regulatory functions provides an explanation of the action for dominant acting oncoproteins. The relevance of the inactivation of the normal functions of pRB and p53 in human cervical carcinogenesis has recently been demonstrated by the analysis of these two genes and their products in a series of HPV-positive and HPV-negative cell lines. These studies support the notion that the inactivation of the normal functions of the tumor suppressor proteins pRB and p53 are important steps in human cervical carcinogenesis, either by mutation or through complex formation with HPV E6 and E7 oncoproteins.