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While peripheral viral loads can be largely controlled by combination antiretroviral therapy, a significant number of people with HIV (PWH) suffer from HIV-associated neurocognitive disorders (HAND). Cocaine use is a major risk factor for becoming HIV infected, and data have shown that HIV+ cocaine user individuals have worse neurocognitive impairments than those observed from either disease alone. The HIV protein Tat and cocaine synergize to cause damage to neurons in the brain, but astrocytes in the central nervous system (CNS) are an understudied population in these individuals. Importantly, astrocytes support neurons metabolically by supplying key metabolites such as lactate and cholesterol to meet the large energy demands of neurons. Astrocyte-derived lactate is taken up by neurons to serve as a key substrate for ATP production. Additionally, the brain requires an intricate balance of cholesterol to support synaptodendritic communications. Disruption of cholesterol supply and energy deficits have been implicated in brain aging and many neurodegenerative diseases including Alzheimer’s disease. There have been reports of altered brain metabolite profiles in PWH indicative of changes in energy homeostasis. We hypothesized that cocaine and Tat work together to disrupt astrocyte energy metabolism. These changes in energy demand compromise the astrocyte’s ability to support neurons leading to neuronal dysfunction and worsening HAND. Our data show that exposure of astrocytes to cocaine and Tat significantly enhances aerobic glycolysis and decreases lactate production. Our findings also demonstrate that cocaine and Tat decrease astrocyte-derived cholesterol, pointing to a deficiency in cholesterol supply and efflux for use by neurons. These findings are supported in the Tat transgenic mouse model of chronic cocaine use. Taken together, these data uncover novel alterations in the bioenergetics pathway in astrocytes exposed to cocaine and the HIV protein, Tat. Results from these studies point to a new pathway in the CNS that may contribute to HAND in HIV+ cocaine users. / Biomedical Sciences