HIV infection and substance use are comorbid conditions that bidirectionally and synergistically influence the deleterious outcomes in people who suffer from substance use disorders (SUD). The persistence and transcriptional reactivation of HIV lead to the development of neuropathological complications. Strategies to address viral latency include silencing of HIV transcription and reactivation and clearance. The goal of this initiative is to support research aimed at (1) identification of targets and pathways by which transcriptional activity of HIV can be suppressed in HIV reservoirs including the CNS in people with SUD, and (2) application of emerging small molecule drug discovery approaches to identify novel compounds that can be utilized as pharmacological probes and as drugs to suppress HIV transcription in people with HIV-SUD comorbidity.