ABSTRACT/PROJECT SUMMARY This proposal employs novel methods to identify key determinants and consequences of concurrent HIV infection and regular cannabis use. We will acquire extensive phenotype data from peripheral and brain markers of immune activation, brain structure, and neuropsychological performance (NP) in persons living with HIV (PLWH) receiving combination anti-retroviral therapy (cART) (80 regular cannabis users and 80 non-users) and HIV uninfected (HIV-) controls (80 regular cannabis users and 80 non-users). Our overall hypothesis is that cannabis use leads to increases in inflammation in the peripheral and brain compartments. We also hypothesize that phenotypic signatures due to regular cannabis use and HIV will be delineated through NP and brain volumetrics. In Aim 1 we hypothesize that regular cannabis use will increase both peripheral and brain immune indices in PLWH on cART. In Aim 2 we hypothesize that regular cannabis use will lead to a worsening of NP and reductions in brain volumetrics in both PLWH on cART and HIV- controls. This proposal will provide key insights into the effects of regular cannabis and HIV on peripheral and brain markers of immune function and NP in PLWH and HIV- controls. These insights are critical for cure strategies and ongoing HIV treatment initiatives.