Project Summary Even in the era of widespread combination antiretroviral therapy, over half of HIV-infected patients experience HIV-associated neurocognitive impairment (NCI). NCI is driven in part by persistent neuro- inflammation with activated monocytes and T cells playing pathogenic roles. Marijuana and cocaine, two of the mostly commonly abused drugs among HIV-infected persons, cause alterations in neural and cognitive functioning, and have significant immunomodulatory effects. While the effects of HIV infection and drug abuse on immune dysfunction and inflammation, brain structure/function, and NCI have been independently studied, the complex interactions between these biological systems are poorly characterized. Our preliminary work suggests that cocaine and marijuana use have discordant effects on NCI in persons with HIV, with differential impacts across domains of cognitive function. In addition, research has shown that stimulants like cocaine induce an activated immune state, whereas marijuana has anti-inflammatory effects. Building on the prior work of our multi-disciplinary team, with complementary expertise in neuroscience, drug addiction, HIV immunology, and computational biology, the proposed research uses a systems biology approach to investigate the effects of cocaine and marijuana on immune function, brain structure/function, and neurocognition in HIV-infected persons. We aim to: (1) identify the independent and joint effects of cocaine and marijuana use on MRI measures of cerebral volume, white matter integrity, and functional connectivity, and on behavioral measures of neurocognition; (2) quantify differences in peripheral and CNS immune function between marijuana and cocaine users; and (3) employ a systems biology approach to integrate immunology, neuroimaging, and behavioral data into a multi-level predictive model. Our guiding hypothesis is that cocaine induces an immune activated state that causes alterations in brain structure/function and cognitive impairment, while marijuana attenuates these effects through anti-inflammatory processes. The sample will include 150 adults with HIV infection who use cocaine only, marijuana only, cocaine and marijuana, or neither drug, comprising 4 distinct groups (~37/group). At study completion, we will have produced a comprehensive, multi-disciplinary dataset, and our systems biology approach will provide significant insights to generate novel hypotheses for future research on the complex biological intersection of HIV and substance use. This proposal addresses both a critical need to identify ?factors that impact differences in neurocognitive impairment in association with specific patterns of substance abuse? [RFA-DA-16-013] and multiple high priority topics for AIDS-designated funding, including investigation of HIV-associated comorbidities such as neurological complications and understanding the basic biology of immune dysfunction and HIV transmission [NOT-15-137]. This innovative project has strong potential to elucidate the complex biological mechanisms through which HIV infection and drug abuse impact NCI, and to identify appropriate targets for novel therapeutics and clinical interventions.