ABSTRACT Approximately 1.2 million people in the US and ~ 37 million people worldwide are living with HIV-1. In spite of considerable progress in HIV/AIDS research, anti-retroviral therapy (ART) remains the only treatment option for HIV-1 infection. While ART has been highly effective in controlling the virus and making HIV infection a manageable disease, the drugs used in the ART regimens cause adverse side effects. Among the most widely prescribed antiretrovirals (ARVs) are integrase strand transfer inhibitors (INSTIs) which block the critical step of HIV-1 integration into host chromosomes. Unfortunately, recent reports suggest association of INSTI prescription with treatment-limiting neuropsychiatric adverse effects. Therefore, understanding the mechanisms that drive neuropsychiatric effects of INSTIs are critically important for the long-term success of ART. The goal of this proposal is to identify the mechanisms of INSTI-associated neuropsychiatric adverse events (NPAEs). Currently, it is recommended that INSTIs be included in all initial regimens for HIV-1 treatment. the most preferred ARVs. Currently approved INSTIs include raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. Although generally reported to be safe and effective there is a growing concern about the adverse metabolic and neuropsychiatric effects associated with the INSTIs. We hypothesize that that INSTI-associated NPAEs are driven by alterations in glutamate and calcium signaling that affect synaptic function and neuronal communication in specific brain circuits. To test this, we propose three specific aims. In Aim 1, we will e lucidate the effects of HIV-1 INSTIs on glutamate neurotransmission. In Aim 2, we will decipher the mechanism of INSTI-induced glutamate neurotransmission. In Aim 3, we will probe the adverse effects of HIV- 1 INSTIs on neuropsychiatric circuitry. To achieve the goals of these specific aims, we have developed a novel approach that combines the expertise in HIV neuropathogenesis, to that of neuroscience and neuropsychiatric disorders and clinical research. Through this multidisciplinary approach, our studies will uncover novel cellular and biochemical pathways that may be targeted to reduce INSTI-associated neuropsychiatric adverse effects. HIV/AIDS disproportionally affects African-Americans and other minorities. ART is the only treatment option available to reduce the disproportionate burden of this deadly disease. Unfortunately, long-term exposure to ART contributes to treatment-limiting NPAEs among HIV-1 positive individuals. Given the rapidly expanding global use of INSTIs to treat HIV, it is critical to understand the mechanisms that drive these NPAEs to reduce the disproportionate impact of HIV/AIDS. Therefore, our proposed studies focused on HIV/AIDS are perfectly aligned with the overall goals of the RCMI program.