The purpose of this FOA is to support exploratory studies developing or using novel tools or technologies or testing novel hypotheses to investigate mechanistic questions in HIV infection, replication, latency, and/or pathogenesis (including neuroHIV) in the context of Substance Use Disorders (SUDs). This initiative focuses on exploration and characterization of signaling pathways that are involved in CNS HIV establishment and expansion. The FOA aims to promote research to investigate the underlying molecular mechanisms by which HIV infection is initiated, established, and maintained in the CNS and to determine how addictive substances modulate HIV infection, latency and the size and persistence of CNS HIV reservoirs.