Role of GRIN2 in ART and SUD associated neurological deficits. - 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 that INSTI use is associated with treatment-limiting neuropsychiatric adverse effects. Evidently, PLHIV are often comorbid with cocaine use disorders (CUD) that exacerbates neuronal deficits. Thus, understanding the combined effects of INSTI-ART and CUD on neuronal dysfunction is critical for the long-term effectiveness of the ART. This proposal will probe the combined neuronal and neuropsychiatric effects of INSTI-based ART and chronic cocaine use. INSTIs are included in all initial ART regimens and are widely prescribed ARVs to control HIV-1 infection worldwide. 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 INSTI-based ART. However, the mechanisms and the pathways that drive INSTI-associated neuronal and neuropsychiatric side effects are unknown. Furthermore, there are key knowledge gaps in our understanding of any additive or synergistic effects of CUD in INSTI-ART associated neurological deficits. We hypothesize that INSTI-ART and cocaine-associated neurocognitive deficits are driven by alterations in glutamate and calcium signaling that affect synaptic function and neuronal communication in specific brain circuits. To test this, we have developed a multi-pronged approach that combines biochemical, genetic, and pharmacologic analysis of neuronal function with electrophysiological studies of neuronal circuits. Using this novel approach, we will test our hypothesis through three specific aims. In Aim 1, we will assess the effects of INSTI-ART regimens on excitatory glutamate neurotransmission. In Aim 2, we will probe the adverse effects of INSTI-ART on neuropsychiatric circuitry. In Aim 3, we will probe the combined effects of INSTI-ART and chronic cocaine use on alterations in synaptic neurotransmission within neuropsychiatric circuitry. To achieve these goals, we have combined the expertise in HIV neuropathogenesis, to that of neuroscience and neuropsychiatric disorders, and clinical research. Together, these studies will comprehensively define the molecular, cellular, and neuronal circuit level effects INSTI-ART and CUD. This new knowledge will promote new and improved therapeutic strategies to reduce the severity of neuronal deficits among ART-adherent people living with HIV.
