Project Summary Abstract There is a critical need to better understand the epidemiology and biology of oral human papillomavirus (HPV) infection in people living with HIV (PLWH). This will, in turn, help identify the pathophysiology leading to HPV- related manifestations such as oral and anal warts as well as oropharyngeal squamous cell carcinoma. This is an exploratory cross-sectional prospective cohort study designed to help address this need. The goal of this study, in line with the mission of the National Institute of Dental and Craniofacial Research (NIDCR), is to identify markers that will help predict, prevent, and ultimately treat HPV infection and its sequelae in PLWH based on underlying biologic, clinical, and socio-behavioral factors. Oral and anal swabs will be obtained from HPV+ and HPV- PLWH to evaluate the microbiome in the two groups. Immune status (CD4 count and viral load) and antiretroviral therapy (ART) regimen will be compared in the two groups and in relation to the microbiome. Clinical findings (oral and anal lesions, diseased, missing, filled teeth) and socio-behavioral factors (sexual practices, tobacco/alcohol exposure) will also be compared in HPV+ and HPV- PLWH. The central hypothesis is that oral HPV co-infection with HIV will correlate with a certain degree of oral and anal microbiome dysbiosis, dysregulated immune status and specific socio-behavioral factors. Specific Aim 1: Elucidate enrichment pathways to further understand oral and anal microbiome dysbiosis in PLWH. Specific Aim 2: Examine immune status as well as ART regimen in PLWH with respect to HPV infection. Specific Aim 3: Characterize the clinical and socio- behavioral aspects that increase risk of HPV infection in PLWH. The proposed study should identify correlates of variables that offer insight into HIV/HPV co-infection. Future research plans will include a prospective longitudinal study to monitor for HPV persistence and the development of cancer in this cohort of PLWH.