ABSTRACT In the United States, it is estimated that more than 9% of people living with HIV acquired the virus through injection of substances or substance abuse-related sexual contact. Although substance use is well known to exacerbate HIV-associated neurotoxicity, there is no prompt treatment for alleviating neurocognitive dysfunctions in HIV-positive individuals. Our proposal is based on significant discoveries regarding the impact of chronic METH and HIV on the neurogenic niche, such as (i) HIV can infect the neural progenitor cells (NPCs) in subventricular zone (SVZ) of the lateral ventricle in mouse brain; (ii) chronic METH and HIV changes microRNA (miRNA) profiles of ex vivo NPCs; and (iii) METH and HIV-disrupted blood-brain barrier (BBB) integrity increases brain inflammation, but it does not stimulate the migration of NPCs in that lesion. The overall goal of this proposal is to investigate a novel mechanism linking the BBB pericytes and NPCs in chronic METH and HIV-induced alterations of NPC migration mediated by miRNAs. In order to evaluate this hypothesis, our transdisciplinary study will focus on the role of miR-21-5p, whose expression is significantly reduced in METH and HIV-exposed mouse SVZ NPCs and plasma samples, in the alteration of SVZ NPCs migration (Aim 1), and the crosstalk between the BBB pericytes and NPCs in response to METH exposure and HIV infection in the brain (Aim 2). We anticipate that this proposed research will demonstrate the potential of restoring the NPC migration to combat the neurotoxic effects of METH and HIV, ultimately improving neurocognitive function by enhancing adult neurogenesis. The focus on the interaction between the brain microvasculature and NPC migration, which influences the development of neurocognitive dysfunctions following chronic METH exposure and HIV infection, is an innovative and cutting-edge conceptual approach. Moreover, given the growing evidence linking miRNA expression alterations to substance abuse and HIV infection, studying the role of miRNAs in METH and HIV-induced altered neurogenesis is crucial and provide new insights into the underlying mechanisms of neurotoxicity and potential therapeutic targets.