HPV is structurally very closely related to the lower animal papillomaviruses (Chapter 4). Un- like HCV (above), the viral genome is relatively stable, with only 1% of genomic variability originating over periods exceeding 105 years (cf. IARC, 1995). HPVs are highly specific for the human, but as yet it has not been possible to readily infect human cells in culture with HPV;
consequently molecular investigations must be done with transfected cells or in artificial human transplants to athymic mice (Kreider et al., 1986). In preneoplastic cervical dysplasia and many CINs, papillomaviruses occur in the circular episomal form; but in malignant neoplasms, inte- gration of the viral genome into the host cell DNA is the rule. A diagram of the organization of the HPV genome and its pattern of integration is seen in Figure 12.16. In comparison with the genome of animal papillomaviruses (Chapter 4), the organization is quite similar, although the integration structure may vary in some neoplasms (Stoler, 1996). Of the genes noted in the fig- ure, E5, E6, and E7 are associated with growth stimulation and the transformation process. L1 and L2 are capsid proteins, and the other E genes are concerned with viral replication and tran- scription (Chapter 4). Thus far, in vitro systems for infection of cells in culture and development of vaccines to HPV have not been developed. On the other hand, transgenic mice expressing one
Figure 12.16 Organization of the HPV genome and pattern of its integration. In low-grade lesions the circular episomal form is dominant. In most neoplasms integration occurs randomly in the host genome, although the viral genome is usually disrupted in the E2 open reading frame, leading to loss of E2 protein transregulatory functions. (After Stoler, 1996, with permission of the author and publisher.)
or more of the critical genes have the potential to increase our knowledge of the pathogenesis and possible immunology of the virus infection (Griep and Lambert, 1994).
The natural history of the development of cervical cancer has been studied in several epi- demiological investigations (cf. IARC, 1995; Melbye and Frisch, 1998). A peak incidence of HPV infection is observed among women aged 20 to 25 years, followed by another peak of high-grade cervical lesions 5 to 10 years later. The incidence of cancer of the cervix declines in women over 50 years of age, after which time increasing incidences of vulvar, penile, and anal cancer, many of which are associated with HPV infection, are seen (Figure 12.17). However, studies in both immunodeficient and immunocompetent women have indicated that HPV infec- tion is followed by the development of dysplastic and intraepithelial neoplasia, the latter ulti- mately developing into invasive carcinoma. This model of HPV pathogenesis suggests that the virus may serve as a promoting agent during its episomal life, transforming into a progressor agent upon integration of the viral genome into the host cell genome (Kashyap and Das, 1998).