The proposal in this application will study the extent and specifics of immune activation, its cardiovascular consequences, and mechanisms as they relate to gut integrity in HIV-infected intravenous (IV) heroin users virologically-suppressed on antiretroviral therapy. Overreaching goals are 1) to define the extent and specifics of immune activation in HV-infected IV heroin users; 2) to define the effect of IV heroin on gut integrity and permeability, and the relationship of gut integrity alteration and immune activation; 3) importantly, to study the reversibility of immune activation, inflammation, and gut dysfunction after cessation of IV heroin, and to that effect, compare two strategies for medication assisted treatment—buprenorphine/naloxone versus methadone maintenance; 4) to study if heightened immune activation associated with active intravenous drug use (IVDU) is associated with higher cardiovascular disease risk, including endothelial dysfunction and arterial inflammation, and if these effects are reversible with buprenorphine/naloxone or methadone. To answer these complex questions an expert team has been assembled with the plan to recruit a cohort of ART-treated, HIV- infected persons who use IV heroin, and very carefully matched HIV-infected controls who have never used IV drugs. A second cohort of ART-treated HIV-infected persons who use IV heroin choosing medication assisted treatment with either buprenorphine/naloxone or methadone to stop using will also be established. These cohorts will be followed serially and data will be collected regarding virologic and immunologic responses to continued IV heroin use versus no IVDU and to buprenorphine/naloxone versus methadone. Levels of cellular activation with phenotyping of T-lymphocytes, as well as levels of soluble markers of immune activation and inflammation will be measured. The effect and reversibility of IVDU on arterial inflammation and endothelial dysfunction will be serially measured, before and after buprenorphine/naloxone or methadone.