PROJECT SUMMARY / ABSTRACT Chronic HIV infection remains a public health challenge with nearly 38 million people worldwide living with HIV/AIDS. Despite the success of antiretroviral therapy in suppressing ongoing viral replication, numerous challenges remain including chronic inflammation and accelerated onset of comorbidities. Better understanding of the mechanisms contributing to these phenomena is imperative to further reduce comorbidities and improve treatment of HIV. The microbiome is comprised of trillions of diverse microbes (bacterial, fungal, viral), and multiple lines of evidence highlight the connections between the microbiome, mucosal immune system, and HIV-related inflammation. While the intestinal microbiome has been the focus of intense research, less is known about the role of the oral microbiome in health and disease. In non-HIV settings, the oral microbiome has been associated with increased risk of inflammation-related comorbidities such as cardiovascular disease. Recent evidence has also highlighted the connection between the oral and gut microbiomes, and increased colonization of aerotolerant “oral” bacteria in the gut has been observed in many inflammatory diseases, including HIV. Studies examining the oral microbiome in the setting of HIV are limited, and none have examined the relationships between oral to gut bacteria translocation, onset of dysbiosis, and systemic inflammation in HIV. We hypothesize that bacterial translocation from the mouth to the gut contributes to the development of dysbiosis in chronic HIV infection. Further, we hypothesize that the oral microbiome contributes to local and systemic inflammation in chronic HIV, and this altered mucosal environment may increase susceptibility for oral infections. Using longitudinal specimens, novel saliva analyses, and epidemiologic clinical outcomes we will systematically address our hypotheses. We propose to: 1) determine the contribution of oral microbiota to gut dysbiosis and systemic inflammation in persons living with HIV; 2) define the relationship between salivary IgA responses to key oral bacteria and local and systemic inflammation; and 3) identify specific oral bacteria that may predict risk of oral sexually transmitted infections (STI) in at-risk persons with and without HIV. This work will help better define the complex relationships between the oral microbiome, inflammation, and infection susceptibility in HIV; a critical step for developing novel strategies and saliva-based monitoring tools to better treat HIV and reduce comorbidities.