Abstract The goal of this study is to understand the role of the oral microbiome and periodontal diseases in oral HPV infection among people with HIV (PWH); the proposed study will also examine immunological underpinnings of oral HPV infection and whether social determinants of health play a role in the oral microbiome and oral HPV infections for PWH. HPV infection has been identified as a carcinogen for oropharyngeal cancer, the most common HPV-associated cancer in the U.S. Among PWH, rates of oral HPV infection, along with oropharyngeal cancer, are significantly higher than in the general population. Yet, the etiology and pathophysiology of oral HPV infection in PWH are not well-documented. The role of oral microbiota has long been recognized in the etiology of many oral infections and diseases. Persistent immune activation and inflammation and impaired oral mucosa epithelial tight junctions from HIV infection and treatment could result in oral microbial dysbiosis, leading to oral HPV infection. However, current evidence on the association between the oral microbiome and oral HPV infection is lacking among PWH. Additionally, as a polymicrobial condition and another primary inflammatory resource, periodontal diseases are most commonly seen in PWH in the face of ART and may facilitate oral HPV infection. Research evaluating the role of periodontal diseases on oral HPV acquisition and persistence is sparse, particularly in the context of the oral microbiome. Furthermore, the oral microbiome is a crucial mediator of inflammation and immune regulation, two major contributors to oral HPV infection. Still, oral mucosa's inflammatory and immune responses to HPV infection are less understood. Therefore, we propose a longitudinal, cohort study of 500 PWH to examine the association among oral microbiome, periodontal diseases, and oral HPV infection. Participants will be followed up to two years with every six months for oral HPV testing and periodontal status and every year for oral microbiome assessments. We will also examine the oral immune and inflammatory responses yearly and investigate the alterations in oral immunological profiling related to oral microbiome and oral HPV infection. Moreover, a total of 86% of our eligible patients are African American, and 52% of them are below the federal poverty level, suggesting the difficulties in receiving health care services and the importance of studying social determinants of health for PWH. Thus, we will also explore the impact of social determinants of health, such as neighborhood conditions, on oral microbiome and oral HPV infection. Findings will provide needed evidence on whether and how the oral microbiome and periodontal disease play a crucial role in oral HPV infection among PWH. The identified oral microbiota will be instrumental in developing targeted interventions to reduce oral HPV infection and subsequently lower HPV-associated HNC incidences among PWH. Addressing critical social determinants ...