Development of a mouse model to test HPV Antiviral compounds

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Project Summary/Abstract Papillomaviruses (PV) cause slowly proliferating epithelial tumors called warts or papillomas. These are very common infections of skin and the cervical, genital, anal, and oral mucosa. Infections with a subset of human and several animal PVs can progress to cervical, anogenital, and oropharyngeal malignancies. Because human PV infections are believed to be species specific, a fully representative model of HPV pathogenesis is not available in a common laboratoryanimal. There is no specifically antiviral therapy for early-stage HPV infection and for HPV-associated cancers. Currently, most treatments involve physical destruction or surgical removal of the infected and nearby tissues. In low resource countries, the lack of testing and scarce availability of surgical procedures results in very high prevalence of HPV-induced cancers. There is a critical unmet need for an in vivo system to test novel therapeutics aimed at eliminating HPV infection. A tractable mouse model to test antiviral agents specifically designed to interrupt HPV protein activities would have a major impact on pre-clinical drug development. The experiments proposed in this R21 grant will investigate the expression and maintenance of HPV-16 genomes in murine cell culture and in live mice. Several forms of HPV-16 genomes will be tested, including the creation of a mouse papillomavirus genome in which the native E6 and E7 genes are replaced by HPV- 16 E6 and E7. These oncoproteins are necessary for both viral genome replication and always expressed in HPV-associated malignancies and are therefore excellent targets for antiviral targeting. If HPV-16 is successfully propagated and the infection persists in mice, these murine models would be an important advance before clinical testing in human. Furthermore, this would also serve as a useful model to investigate the functions of HPV oncoproteins in genome maintenance and neoplastic progression. An antiviral treatment that cures early and persistent HPV-16 infections would reduce the risk and burden of progression to cancer that afflicts millions of people throughout the world.