Substance use needs to be better incorporated into interventions for the engagement and retention of sexual minority persons in prevention and care with attention to emergent interventions such as long-acting PrEP. Social determinants of health associated with HIV and problematic substance use such as homelessness and criminal justice involvement also demonstrate disproportionate impact among sexual and gender minorities and need attention. Changing self-definition of sexual minority status has implications for outreach and provider stigma and needs to be better integrated into interventions. This initiative will address these gap areas and support epidemiologic, intervention, and implementation research that incorporates attention to HIV as a syndemic including comorbidities such as STIs, HCV, and psychiatric disorder.