Project Summary/Abstract Human immunodeficiency virus-1 (HIV) enters the central nervous system (CNS) early after primary infection and results in a spectrum of cognitive deficits, collectively termed HIV associated neurocognitive disorders (HAND). While successful in reducing peripheral viral loads to undetectable levels, antiretroviral therapy (ART) does not effectively quell CNS viremia to the same extent. As a result, ART has not decreased the prevalence of HAND, which continues to increase as the life expectancy for seropositive individuals rises. HIV-infected substance abusers exhibit more severe cognitive impairment compared with their non-drug abusing counterparts. Specifically, cocaine use is associated with an accelerated incidence and progression of HAND. This occurs, in part, due to cocaine-mediated increases in HIV replication and resultant blood-brain barrier perturbations, alterations in ART metabolism, and neuroinflammatory responses that contribute to the sequelae characteristic of HAND. To understand more fully the impact of cocaine use on the pathogenesis of HAND, I will examine two major mechanisms by which cocaine may interfere with ART effectiveness in the CNS. I will evaluate the transport of ART across the blood-brain barrier in the context of cocaine, focusing on the expression and function of influx and efflux transporters. Additionally, I will characterize the association between polymorphisms in cytochrome P450 drug metabolizing enzymes and HAND in HIV-infected individuals who currently consume illicit substances, as well as those without current substance abuse.