Drug abusers account for a substantial proportion of AIDS cases globally. In fact, approximately 10% of new HIV infections worldwide are attributable to injecting drug use, often of an opiate such as heroin. HIV clade C viruses are responsible for nearly half of the global infections and more than 95% of the infections in India. The innate ability of clade C in establishing an expanding epidemic could be ascribed to its unique biological properties, coupled with co-morbidity of drug abuse, which in turn, could influence the HIV LTR genetic polymorphism. We have recently demonstrated the emergence of 4 NF-?B site promoter variant strains in the subtype C in India. The variant viral strains acquire the molecular strategy of attaining an additional NF-?B (3 sites in the wild type & 4 in the variant strains) or RBEIII (onein the wild type & 2 in the variant strains) binding sites (TFBS) leading to enhanced transcriptional potency of the viral promoter. The TFBS duplication is associated with rapid expansion of the variant virus strains in India over the past decade. In fact, the prevalence of the 4-?B strains i India has increased from 1-2% during 2000-2003 to a staggering 30-35% a decade later. The ability to duplicate the NF-?B motifs appears to be unique to subtype C. Based on these observations, we hypothesize that 4-?B strains of subtype C are more infectious leading to increased immune activation, end-organ pathogenesis and latency in the context of opiates. No systemic studies have assessed the impact of viral variant generation on disease progression, and/or end-organ involvement specifically in the CNS. Such longitudinal studies can only be possible in an animal model of HIV infection and opiate abuse. This proposal brings together investigators with unique strengths in molecular virology, macaque pathogenesis and substance abuse to answer these crucial questions while also addressing the relevance in the context of clade B and C viruses. Specifically, two aims are proposed. SA1: To assess the in vitro replication competence of SHIV clones containing 1, 2, 3 or 4 NF-?B binding sites in the promoter as well as env sequences of both clades B and C viruses. SA 2a: To assess the immune responses and disease pathogenesis in Indian rhesus macaques infected with the SHIV clones (clade B vs. C viruses - generated in SA1) in the absence or presence of ART & opiate dependence. SA 2b: To evaluate the influence of the NF-kB number on viral latency in the presence of ART and opiates.