Project Summary/Abstract In sub-Saharan Africa (SSA), Kaposi’s sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi’s sarcoma (KS), is endemic and HIV incidence is high making KS one of the most common cancers in adults associated with high mortality, even in the antiretroviral therapy (ART) era. Although oral lesions are common among AIDS-KS patients, the effects of HIV infection on the oral environment and KSHV reactivation in the oral cavity before KS development are completely unknown. Using innovative and validated techniques this study will be the first to test the hypothesis that alterations in the oral environment during HIV infection are a critical determinant of KSHV reactivation and increased KSHV shedding in the oral cavity. I propose a large adequately powered longitudinal study of 600 Ugandan adult males and females followed over two years from three groups: people living with HIV (PLWH) on long term ART, newly diagnosed ART-naïve PLWH, and HIV uninfected. Participants will be enrolled at the General Population Cohort (GPC) in rural Uganda where KSHV seroprevalence is among the highest in the world and at The AIDS Support Organization (TASO) and AIDS Healthcare Foundation (AHF) Uganda Cares, both longstanding HIV care clinics which serve the GPC area. Oral health examinations will be completed to identify whether PLWH exhibit markers of oral disease including gingivitis and periodontitis, resulting in increased KSHV reactivation and higher KSHV viral loads in saliva (shedders). Oral fluids will be collected to identify whether higher oral inflammatory markers, and lower KSHV- specific IgA are associated with oral KSHV shedding. To capture the role of HIV on changes causing oral microbiome dysbiosis in the oral cavity and continued effects on oral reactivation and shedding of KSHV, we will sequence the V1V3 regions of 16s rRNA, which gives high resolution power to differentiate species in the oral microbiome. The findings produced by this study are truly unique and will be fundamental in identifying whether markers of oral disease, oral mucosal inflammation, reduced immune control in the oral cavity, and oral microbiome dysbiosis are factors leading to KSHV reactivation in the oral cavity prior to KS development. There is an immense gap in the research with regards to the effects of oral health and the oral environment on KSHV reactivation and KS development. We will incorporate an exceptional multi-disciplinary team of experts with innovative and validated techniques to collect truly unique data on oral health and oral immune response indicators from a rural population in SSA. The inventive direction of this proposal combined with the critical need to identify effects of the oral environment on oral KSHV reactivation and shedding, information needed to further the field of research on interventions and therapeutics for KS in PLWH, makes my proposal the perfect fit for this Catalyst award. The information acquired w...