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these are early or mild dysplasias. Severe dysplasia is less common and tends to occur in older women, as though there were changes in the cells during persistent infection over a period of years that leads to dysplasia. Presumably this includes virus-specific changes, such as integration of the viral DNA into the host genome, and possibly some cell-specific changes as well.

Viral Gene Products. In cell lines derived from cervical tumors, there is a preferential retention and expression of three oncogenes from the high-risk HPV. Two genes (E6 and E7) in collaboration with each other can establish immortalization of human keratocytes grown in culture: the E6 product binds to and inactivates the p53 tumor-suppressor protein; the E7 product binds to and inactivates the pRB tumor-suppressor protein. These properties are significantly more active in high-risk than in low-risk HPVs. A third transforming gene of HPV is E5, whose product appears to activate the growth-factor receptors; it is not always found in the malignant tumors themselves, but it may play a role in initiating the lesions.

Animal studies suggest that immunization with E6 and E7 does not prevent lesions, but the lesions do regress faster. As a result, trials are now being conducted to evaluate a therapeutic vaccine based on differing combinations of E6 and E7.

Barriers to Vaccine Development. Several problems limit attempts to understand HPV infection and develop a vaccine. Perhaps the most important is the lack of a system to propagate HPV in vitro. Second, researchers have not been able to produce preparative quantities of purified viral capsid proteins. Third, immune parameters have not generally correlated with the benign infection antibodies to E6, E7, E2, and other viral proteins. In addition, there is no animal model of HPV infection—the productive infection is species-specific, although there are several animal systems that might eventually be used as models.

Approaches to Vaccine Development. Most attention has focused on the development of a subunit vaccine. Work at the Laboratory of Cellular Oncology at the National Cancer Institute (NCI) has focused on the two viral structural proteins, major capsid protein L1 and minor capsid protein L2. Researchers found that when they expressed the bovine papillomavirus (BPV) L1 gene in recombinant baculovirus in insect cells, it was sufficient to cause self-assembly of virus-like particles (VLPs) —essentially empty capsid that do not contain the viral genome. When L2 was added to this insect cell system, there was no major differences in immunogenicity, but there was more efficient assembly of VLPs. This self-assembly process can be carried out with HPV, producing VLPs that do not contain the HPV genome. The BPV system now provides the major in vitro test for infection, a conformational test for antibodies to HPV-16 VLPs.

When rabbits are immunized with authentic BPV virions, it induces very high levels of neutralizing antibodies, more than 105 titer. VLPs, whether L1 or L1-plus-L2, induce similarly high levels of neutralizing antibodies. When the

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