Project Summary/Abstract Males living with HIV are estimated to be at a 2- to 5-fold higher risk of developing human papillomavirus- related oropharyngeal cancer (HPV-OPC) compared to the general population, with up to 90% of cases attributed to oral high-risk (oHR)-HPV16. Because precancerous lesions are a challenge to diagnose and clinicians have no reliable means of identifying vulnerable patients, effective interventions will require a thorough understanding of the natural history of oHR-HPV. The presence of persistent non-oral HR-HPV precedes precancerous lesion development in other HPV-related cancers; the same may be true for oHR-HPV. HIV and anti-retroviral therapy (ART) may alter the oral microbiome and give rise to oral lesions and periodontal disease, creating an immune microenvironment conducive to persistent oHR-HPV that ultimately increases the risk for HPV-OPC. Predictors of oHR-HPV infection and persistence could serve as detection markers for HPV-OPC to prompt preventive treatment early in disease progression when treatment outcomes are most favorable. We propose to conduct a prospective study to characterize longitudinal events of oHR- HPV among an at-risk population (CLEAR). We will leverage our longstanding multidisciplinary and international collaboration and the established cohort receiving care at the sexual and gender minority-friendly TRUST clinic in Nigeria. A total of 1,200 HPV-unvaccinated Nigerian non-heterosexual males who perform oral sex and are living with or without HIV will be screened for oHR-HPV. A subset of 500 males, including those with a prevalent oHR-HPV will be followed every 3 months for up to 2 years. We will collect oral gargle and blood samples to detect incident and persistent oHR-HPV infection; measure CD4, HIV viral load, and the oral microbiome; characterize oral sex practices; and perform dental examinations to document periodontal disease, oral lesions, and dental caries. We will determine the association between HIV clinical markers and oral-anogenital contact and the prevalence of oHR-HPV (AIM 1). We will compare the time course of oHR-HPV as a function of HIV status (AIM 2). We will evaluate the relationship between dental phenotypes, the oral microbiome, HIV clinical measures, and oHR-HPV infection (AIM 3). Understanding the oHR-HPV burden, time course of infection, and oral cavity indicators of the immune microenvironment in the context of HIV will generate robust data needed to help inform predictive models and develop rational risk-stratified screening algorithms to help mitigate risk of HPV-OPC in males living with HIV.