Perceived relationships regarding adherence, risk of resistance, and clinical impact of resistance drive concerns about providing HIV therapy to impoverished populations. While these debates first focused on drug users and the homeless, now they focus on resource-constrained countries. Critical factors that determine drug resistance and treatment failure such as adherence, stage of disease at treatment initiation, T cell activation, viral subtype and pharmacogenomic determinants of drug resistance likely differ in resource-rich and resource-constrained settings. Our group has characterized adherence and resistance to non-boosted protease inhibitor antiretroviral therapy in San Francisco and we have begun to characterize adherence and treatment response to HIV antiretroviral therapy in Uganda. We propose to study the behavioral and biologic determinants of HIV antiretroviral drug resistance and disease progression in two prospective 500-person observational cohorts on HIV antiretroviral therapy: the Research in Access to Care in the Homeless (REACH) Cohort and the Uganda Antiretroviral Treatment Outcomes (UARTO) Cohort. We will leverage an R-21 NIAAA funded study to characterize adherence, treatment response and drug resistance in Uganda. We will continue to follow the REACH Cohort to characterize adherence-resistance relationships to new antiretroviral medications and to determine the extent that resistant virus speeds disease progression and death. Using comparable measures of objective adherence, T cell activation, viral suppression, viral subtype and immunologic response, we will utilize the behavioral and biologic variation in the two cohorts to characterize fundamental pathways of treatment failure and drug resistance. To better guide therapy in both settings, these studies will further our understanding of drug resistance, including its causes, its extent and the role it plays in disease progression and death.