The papillomaviruses are a family of DNA viruses that induce cutaneous papillomas or warts in a variety of mammals, including humans (for a review, see Howley, 1996). The Shope papillo- mavirus was an early if not the first example of a DNA tumor virus (Shope, 1932). This virus normally causes warts in its natural host, the cottontail rabbit. Domestic rabbits infected with the Shope papillomavirus will also develop warts, which develop to carcinomas in many instances. The bovine papillomaviruses (BPV) and human papillomaviruses (HPV) are the best experimen-
Figure 4.10 Genetic organization of SV40 genome. The genome of SV40 is a circular, double-stranded DNA of 5243 bp. The VP-1, 2, and 3 genes encode virion structural proteins. The small T and large T genes encode viral regulatory proteins. The protein encoded by the large T gene is named large T antigen. Rodent cells are not permissive for SV40 replication. At a low frequency, SV40 will transform rodent cells. All transformed cell clones contain an integrated, partial copy of the SV40 genome that expresses large T anti- gen. Large T antigen is necessary and sufficient for the transformation of rodent cells. (Adapted from Levine, 1992, with permission of author and publisher.)
tally studied members of this virus family. To date over 70 different HPVs and six BPVs have been described. In humans, some of the HPVs cause benign neoplasms, such as warts. Other human papillomaviruses are believed to be the causative agent of anogenital carcinomas, such as cervical cancer. Most anogenital cancers in humans have an integrated copy of HPV, primarily of the HPV-16 and HPV-18 subtypes. BPV-1 is the best-studied bovine family member. BPV causes benign warts in cattle. Both BPV-1 and HPV-16 and -18 cause transformation of cells in culture (Dvoretzky et al., 1980). The study of the ability of these viruses to transform cells has led to the identification of the genes that contribute to this phenotype.
The papillomavirus genome is covalently closed circular DNA of approximately 8 kb (Figure 4.11). The genetic organization of BPV and HPV is very similar, with some minor dif- ferences. BPV-1 has 10 genes, while the HPVs have nine, which are located in a clockwise ori-
Figure 4.11 Genetic organization of human papillomavirus (type 16). The genome is a circular, double- stranded DNA molecule of 7,904 bp. The genes are E1 to E7, L1 and L2. The viral long control region (LCR) contains transcriptional and replication regulatory elements. Genetic organization of BPV-1 is simi- lar, with the presence of an additional gene, E8. With HPV-16, E6 and E7 are the major transforming genes. The E3 gene, which is not indicated above, is not a consistent feature of all HPV isolates. (Adapted from Levine, 1992, with permission of author and publisher.)
entation. Two of the genes, L1 and L2, code for subunits of the virion capsid. The remaining genes are named E1 through E8. These code for non-structural proteins required for the viral life cycle. In terms of transformation of cells in culture, BPV and HPV share common features but also have some key differences. BPV-1 will transform the two mouse cell lines, C127 and NIH 3T3, in culture. In the transformed cell, BPV-1 DNA is commonly found as a multicopy plas- mid, and integration is not required for the transformed state (Law et al., 1981). Three BPV-1 proteins, E5, E6, and E7 that contribute to the transforming potential of BPV-1 (Yang et al.,1985). BPV-1 E5 is believed to make the most significant contribution to the transformed state, with E6 and E7 playing ancillary roles (Schiller et al., 1986; Neary and DiMaio, 1989). BPV-1 E5 is a membrane protein that influences signaling of the platelet-derived growth factor (PDGF) receptor to mediate transformation (Schlegel et al., 1986; Petti et al., 1991). In contrast, transfor-
mation by the oncogenic HPVs is mediated by the E6 and E7 genes (Bedell et al., 1987; Phelps et al., 1988). E5 does not appear to play a role. The E6 and E7 proteins of the high risk HPVs act in a fashion similar to SV40 large T antigen and adenovirus E1A and E1B proteins. E6 leads to the degradation of the p53 tumor suppressor protein, while E7 binds to Rb to interfere with its tumor suppressor functions (Dyson et al., 1989; Scheffner et al., 1990; Werness et al., 1990).