Infection with HIV increases susceptibility to opportunistic infections and cancer. The risk of oral and oropharyngeal carcinomas is increased in HIV-seropositive patients reflecting a higher rate of oral human papillomavirus (HPV) infection. Recent data indicates that the oral cavity contains a plethora of HPV species including beta and gamma-HPV types, previously associated with skin neoplasias. We recently found that detection of beta and gamma-HPV in the oral cavity was associated with increased risks of incident head and neck cancer. This suggests an etiologic association for beta and gamma-HPV types in the oral cavity, especially among HIV-infected populations who are at increased risk of developing a variety of virally induced head and neck tumors. However, to date, very little is known about the natural history of oral infection with beta and gamma-HPV types in either HIV-positive or HIV-negative populations. We will leverage the clinical infrastructure from an existing NIDCR funded study, and a collaboration with the University of Michigan Head and Neck SPORE supplement expanding the NIDCR project, to test repeated oral rinse and brush samples collected from 400 HIV-positive and HIV-negative patients for multiple beta and gamma-HPV types by next-generation sequencing. Study participants are followed prospectively for a period of up to 3 years, and complete a survey consisting of questions related to tobacco and alcohol use, sexual practices, and oral hygiene. Clinical data related to control of HIV infection and history of other chronic infections are collected. Using this longitudinal data, we propose to: 1) assess and compare HPV type distribution and viral activation status for beta- and gamma-HPV types in the oral cavity among HIV-positive and HIV-negative individuals, and 2) determine and compare the incidence and persistence of, and risk factors for, beta- and gamma-HPV infections in the oral cavity among HIV-positive and HIV-negative individuals. At the completion of this project, we will have precise estimates of the incidence and persistence of oral beta- and gamma-HPV infections, and identified risk factors for incident and persistent infection in HIV-positive and HIV-negative individuals from an ethnically diverse high-risk population. In addition, this study will provide information to guide consideration of development of new HPV vaccines to prevent oral/oropharyngeal cancers.