Papillomaviruses play a critical role in inducing malignant epithelial tumors of the oral and genital tract in humans. In our first grant awarded by the National Cancer Institute, we developed a canine model for evaluating the efficacy of vaccines in preventing infection by a mucosotropic papillomavirus (COPV). Our results indicated that the systemic administration of an L1 capsid protein vaccine was completely effective in preventing oral tumors. In addition, the studies demonstrated the critical role of L1 conformation and L1 type for inducing protective humoral (IgG) immunity. The eventual application of an L1 vaccine for human mucosotropic viruses will have a significant positive impact on women's health care and on expenditures by the health care system for detecting and treating papillomavirus-induced malignancies. In the current grant we propose to define the molecular determinants of L1 which are required for native conformation and for successful vaccination against COPV infection. We also propose to explore the L1 domains participating in virion assembly and type-specific antigenicity. In addition, we also plan to extend the canine model to the analysis of genital lesions so that we can investigate the role of host hormonal status in the initiation and growth of COPV-induced tumors. Finally, we will also develop techniques to assay COPV and HPV infectivity in-vitro so that it will be possible to inexpensively detect and titer anti-viral antibodies. In summary, the goals of this proposal are to define the molecular requirements for L1 immunogenicity and to extend the canine model to the analysis of genital tumors in order to precisely mimic the biology of human papillomavirus-induced genital neoplasia.
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