Human papillomavirus (HPV) infections cause approximately 5% of all human cancers. A group of “high-risk” alpha-HPVs are etiologic agents of cervical carcinoma, other anogenital cancers and as well as head and neck cancers. The beta-HPVs cause cutaneous squamous cell carcinomas (cSCCs) in patients with a rare hereditary skin disorder, epidermodysplasia verruciformis (EV), and in the rapidly growing population of organ-transplant and other chronically immunosuppressed patients. The gamma-HPVs have also been detected in cSCCs. Even though prophylactic vaccines that protect from infections with most cancer-associated alpha-HPVs are on the market, US vaccination rates have remained low, and because cancers arise years to decades after the initial infection, vaccination will not have an immediate impact on HPV cancer rates. Moreover, these vaccines do not offer protection from beta- and gamma-HPV infections and, hence, they will not impact cSCCs triggered by these HPVs. The E6 and E7 proteins encoded by the cancer-associated alpha- and beta-HPVs have oncogenic activities and function by binding to and functionally subverting host cellular signaling proteins. Because HPVs do not replicate in heterologous hosts, there have only been very few studies that probed the relevance of papillomavirus E6 and E7 cellular targets for viral pathogenesis and carcinogenesis in vivo. The discovery of Mus musculus Papillomavirus 1 (MmuPV1), which infects common laboratory mouse strains, finally allows papillomavirus pathogenesis and carcinogenesis studies in vivo and in a genetically tractable host. This proposal leverages the expertise of the Lambert group who has established an MmuPV1 infection/pathogenesis model for cutaneous and mucosal sites and the Munger lab who has identified MmuPV1 E6- and E7-associated cellular proteins and validated many of these interactions in cell-based assays. Our proposal is based on the hypothesis that MmuPV1 is a model to investigate HPV pathogenesis and carcinogenesis, and these insights will be key to identifying targets for antiviral therapy. We will investigate the importance of MmuPV1 E6 inhibiting NOTCH and TGF-beta signaling, and E7 subverting the retinoblastoma tumor suppressor RB1, as well as E6 and E7 mediated subversion of innate immune signaling by the RIG-I/MAVS and cGAS/STING, respectively, for cutaneous pathogenesis and carcinogenesis.