PROJECT SUMMARY HIV infection, as well as exposure to opioids including intravenous heroin, are associated with systemic immune activation including increased microbial translocation from the gut. The overall objective of this study is to provide clinical evidence on the detrimental link between kinetics and characteristics of immune reconstitution (microbial translocation, residual immune activation, retained HIV expression) in HIV-1 infected people who inject drugs (PWIDs) and sustain interaction with the μ-opioid receptor (MOR) while on antiretroviral therapy (ART). Defining the impact of continued MOR engagement after ART initiation is of relevance to addiction treatment as maintenance-assisted treatment options include using a MOR agonist (methadone, MET) or a MOR antagonist (long-acting naltrexone, XR-NTX). Notably, the effect of oral MET, which is widely used in maintenance treatment, on ART-mediated immune reconstitution is unknown. Based on preliminary data showing higher microbial translocation, immune activation, and active HIV transcription in ART-suppressed PWID on MET over XR-NTR, we will test the primary hypothesis that chronic engagement of mu-opioid receptor by a full MOR agonist (MET) while on ART will result in reduced rates and magnitude of microbial translocation, with sustained immune activation and inflammation associated with increased levels of persistent HIV (i.e., integrated HIV DNA, cell-associated HIV RNA) when compared to a full MOR antagonist (XR-NTX) in spite of viral suppression. Specifically, we will test these hypotheses in the following specific aims: Specific Aim 1. Defining the impact of long-term MOR stimulation (MET) or blockage (XR-NTX) on the kinetics and extent of immune reconstitution in PWID initiating ART. To this end, we will also compare 48 week changes on residual immune activation, microbial translocation, and systemic inflammation in a cohort of PWID with chronic HIV infection initiating ART, randomized 1:1 to either MET or XR-NTX. sCD14 level change after ART will serve as the primary end-point variable. Specific Aim 2. Defining the clinical and virologic correlates of 48 week treatment with MOR agonists (MET) and antagonists (XR-NTX), by studying effect of the intervention on CD4, adherence to ART, acceptability of MAT, as well as retention in care. Changes in persistent HIV measures will also be measured (i.e., persistence of viral RNA and DNA species in PBMC, etc.). Given the high prevalence of HIV-infected heroin users starting ART and opioid addition therapy, Vietnam is an ideal setting to complete the proposed study to provide generalizable proof-of-concept data in support of future long-term clinical outcome studies. This study ...