Neurocognitive impairment (NCI) continues to be a frequent complication of HIV infection. Drug abuse represents one of the risk factors for persisting NCI. In this study we propose to examine one potential mechanism whereby heroin abuse increases risk for NCI in HIV infected persons. We hypothesize that the physiological stress of repeated abstinence syndromes that heroin addicts experience may trigger physiologic events that favor viral injury of the brain. Specifically, we propose that abstinence induces significant hypothalamic-pituitary-adrenal axis (HPA) and sympathoadrenal medullary (SAM) activation leading to immunological changes, e.g., increased lymphocyte and monocyte activation and trafficking across the blood-brain-barrier, as well as induction of various proinflammatory molecules that may also favor neuroinflammation. To establish a proof of principle for this hypothesis we propose a R21 preliminary study, which will examine 50 heroin-detoxifying individuals in Russia. Medical, virologic, neuroendocrine, immune, and virologic assays will be conducted at 3 time points - immediately upon beginning detoxification; 7 days later; and approximately 4 weeks after initial detoxification. We shall relate changes in HPA and SAM activation to fluxes in proinflammatory biomarkers and alterations in virologic control, and link these to fluctuations in neurocognitive impairment. The research will be conducted via a collaboration between investigators at the Valdman Institute of Pharmacology, Pavlov State Medical University, Saint Petersburg, Russia, the HIV Neurobehavioral Research Program at the University of California, San Diego, with consultation from Dr. George Woody at the University of Pennsylvania. Performing this research in Russia is opportune for two reasons: 1) heroin use is the major HIV risk factor in Eastern Europe, hence this work has high relevance; 2) heroin detox practice in Russia dictates symptomatic management, but not opioid substitution (e.g., methadone). This makes it feasible to study withdrawal effects in a clinical setting. If successful in establishing this collaboration and providing initial proof of principle, this study ay lead to more mature research on effects of instituting antiretroviral treatment and naltrexone therapy to reduce likelihood of neurotoxic events during detoxification.