IMPACT OF METHAMPHETAMINE ON MICROBIOME DYSBIOSIS AND NEURO-DYSFUNCTION IN SIV INFECTED RHESUS MACAQUES ON ANTIRETROVIRAL THERAPY - PROJECT SUMMARY ALTHOUGH POTENT ANTIRETROVIRAL THERAPY (ART) SUPPRESSES HIV REPLICATION TO UNDETECTABLE LEVELS IN PERIPHERAL BLOOD IN PEOPLE WITH HIV (PWH), INDIVIDUALS ON ART CONTINUE TO EXPERIENCE SYSTEMIC CHRONIC INFLAMMATION AND INCREASED PREVALENCE OF COMORBIDITIES. HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND) STILL OCCUR IN PWH ON ART, AND THE UNDERLYING MECHANISMS ARE LARGELY UNKNOWN. RECENT STUDIES DEMONSTRATE THAT THE GUT-BRAIN AXIS MAY PLAY A CRITICAL ROLE IN CONTRIBUTING TO HAND. FURTHERMORE, FOR THOSE WHO EXPERIENCE SUBSTANCE USE DISORDERS, SUCH AS METHAMPHETAMINE (METH) USE DISORDER, THE HAND PREVALENCE IS EVEN HIGHER. DURING HIV INFECTION, METH EXACERBATES THE PATHOGENESIS OF THE VIRUS WHILE DECREASING THE EFFECTIVENESS OF ART. EVIDENCE SHOWS THAT BOTH HIV INFECTION AND METH USE DISORDER CAUSE GUT DYSBIOSIS. DYSBIOSIS HAS THE POTENTIAL TO WORSEN PATHOGENESIS BECAUSE THE GUT MICROBIOME COMMUNICATES WITH THE BRAIN VIA THE GUT-BRAIN AXIS AND MEDIATES THE IMMUNE SYSTEM FUNCTION. A BETTER UNDERSTANDING OF HOW METH USE DISORDER CONTRIBUTES TO HAND IN PWH ON ART IS ESSENTIAL. THIS PROPOSAL WILL TEST A CENTRAL HYPOTHESIS THAT METH USE DISORDER CONTRIBUTES TO HIV-ASSOCIATED NEUROLOGICAL DYSFUNCTION OR ONSET OF HAND THROUGH ALTERATIONS OF THE MICROBIOME AND ITS METABOLITES VIA THE GUT- BRAIN AXIS. THIS WILL BE INVESTIGATED USING THE METH+/SIV+ART+ NONHUMAN PRIMATE MODEL TO FIRSTLY DETERMINING THE EFFECT OF METH ON GUT MICROBIOME BALANCE AND ITS ASSOCIATION WITH NEUROLOGICAL DYSFUNCTION (AIM 1), AND THEN CHARACTERIZING THE BEHAVIORAL AND PHYSIOLOGICAL IMPACTS OF METH USE DISORDER (AIM 2). THE PROPOSED RESEARCH WILL BE CONDUCTED AT TEXAS BIOMEDICAL RESEARCH INSTITUTE, WHICH OFFERS NUMEROUS TRAINING OPPORTUNITIES, AVAILABLE RESOURCES, AND EXPERIENCED MENTORS THAT WILL ENSURE SUCCESSFUL COMPLETION OF THE PROJECT. OVERALL, THE PROPOSED RESEARCH WILL EXPLORE HOW METH IMPACTS THESE PROCESSES VIA THE GUT-BRAIN AXIS BY EXAMINING CHANGES IN THE MICROBIOME AND METABOLITES, AND THEIR SUBSEQUENT EFFECTS ON THE BRAIN. RESULTS GENERATED FROM THIS PROJECT WILL SHED LIGHT ON NOVEL NEW MECHANISMS AND PROVIDE VALUABLE INFORMATION FOR FUTURE THERAPEUTICS AIMED AT IMPROVING CNS FUNCTION IN PWH WITH METH USE DISORDER.