ABSTRACT Oropharyngeal cancers (OPC) are increasing in the United States and in many regions globally. There are marked differences in the incidence rates of OPC among the United States (US), Puerto Rico (PR), and Mexico (MX) (2.4, 1.9, and 0.23 per 100,000, respectively). Human Papillomavirus (HPV) accounts for over 70% of OPC and people living with Human Immunodeficiency Virus (PLWH) have a 2-3 fold higher risk of prevalent oral HPV infection and 2-6 fold-higher risk of OPC than HIV-uninfected individuals. While studies have associated severity of immunosuppression (CD4/CD8 ratio) with higher prevalence of oral HPV infection, excess risk among PLWH suggests that additional factors may facilitate HPV transmission and persistence, contributing to HPV-specific immune deficiency and subsequent cancer. Nonetheless, the persistence and clearance rates of oral HPV among PLWH are understudied. Our long-term goal is to investigate biological, clinical, and sociocultural factors contributing to disparities, ethnic differences and increased risk of OPC in Hispanic PLWH; essential information for OPC prevention efforts. While Hispanic PLWH are at increased risk of oral HPV infection and OPC, Hispanic populations differ in genetic background, geographic location, diet, lifestyle and other socio-cultural behaviors. Using the infrastructure of the California-MX-PR (CAMPO) Consortium Clinical Trials Program” (U54CA242646), we will perform a multicenter cohort study to achieve our objective of understanding the interplay of biological, clinical and socio-cultural factors contributing to the higher incidence and persistence of oral HPV infection in the context of HIV infection. Specific aims are: (1) To assess baseline prevalence, incidence, clearance, and persistence rates of oropharyngeal HPV infection among Hispanics PLWH in MX, PR and San Francisco (US); (2) To determine the impact of biological factors (i.e. genetic ancestry, oral microbiota, and HPV methylation) on oral HPV infection acquisition, persistence, and clearance among PLWH and (3) To evaluate the impact of clinical (i.e. years living with HIV, ART use, oral hygiene, periodontitis, anogenital HPV infection, immune dysfunction) and socio-cultural (i.e. smoking, diet, sexual behaviors, socioeconomic status) factors on oral HPV infection acquisition, persistence, and clearance among PLWH. We will recruit 600 Hispanic PLWH in MX, PR, and San Francisco (200 in each study site). These individuals will complete a baseline visit and 5 additional follow-up visits every 4 months: for a complete follow-up period of 20 months. Data collection procedures will include oral evaluation for periodontal disease assessment, mouthwash samples for type-specific HPV determination, saliva samples for oral microbiome and HPV-methylation analysis, and blood samples for CD4/CD8 and ancestry assessment. Baseline and follow-up surveys will also provide information on relevant socio-cultural covariates. Given the relevance o...