Project Summary: Young men who have sex with men (YMSM) have been found to have significantly higher levels of systemic inflammation than their heterosexual peers. Left unchecked, prolonged exposure to inflammation has been shown to lead to several health issues including cardiovascular disease, diabetes, and colorectal cancer. YMSM are also experiencing two intertwined epidemics of HIV diagnoses and substance use while also being prone to unique forms of stress and stigma (e.g. sexual orientation related discrimination). This added stress may then lead to increased depression, anxiety, and substance use, each of which has been associated with inflammation and increased participation in risk behaviors associated with HIV acquisition. Further, increased inflammation may itself be a host risk factor for HIV infection, making it a potential target for reducing the incidence of HIV. Currently, there is a dearth of research focused on understanding why YMSM are experiencing elevated inflammation, particularly in the context of substance use, stress, and HIV. The proposed study will utilize data from a large racially/ethnically diverse cohort of YMSM from a NIDA-funded U01. The RADAR study has collected two biomarkers for inflammation: C-reactive protein (CRP) and pro- inflammatory cytokines. CRP and cytokine data have been collected on participants diagnosed with HIV. CRP has also been collected on a matched set of HIV-negative participants; as part of this proposal, cytokine data will be collected and assayed for matched HIV-negative participants. The overarching scientific goal for this NRSA is to examine putative explanatory factors for variability in inflammation among YMSM. I will accomplish this goal by studying: (1) the influence of substance use on systemic inflammation; (2) whether HIV-diagnosis moderates the relationship between substance use and inflammation; (3) the influence of perceived stress and stigma (e.g. internalized stigma, sexual identity concealment, etc) on systemic inflammation; and (4) whether the effects of perceived stress or stigma are mediated by substance use. This proposal represents formative research on systemic inflammation YMSM in the context of substance use, stress/stigma, and HIV. This is a necessary first step in order to reduce the observed disparity in systemic inflammation in this population as a means of reducing HIV transmission. Findings from this study will inform the applicant?s future research as well as our understanding of health disparities by the influences of substance use, stress, and HIV on inflammation in this high-risk population.