Project Summary/Abstract Gay/bisexual/transgender youth (GBTY) and homeless youth (HY) in large metropolitan areas in the U.S., including Los Angeles (LA) and New Orleans (NO), have the highest prevalence of HIV in the U.S. adolescent population. Efforts to engage and retain these at risk youth into the prevention and treatment cascades have generally failed with many not identified as HIV infected or at risk. We propose a multi-disciplinary approach of community outreach, behavioral intervention, and prospective surveillance in LA and NO to identify undiagnosed youth at risk/ infected with HIV & STI. Emerging data of perinatal “Mississippi baby,” a French adolescent with prolonged HIV remission, and adults with acute HIV treatment with early potent ARV have shown that early and sustained viral suppression is associated with a decrease and accelerated decay of HIV reservoirs (VR), which is likely a predictor of long term HIV control and drug free remission. This contrasts with treatment of already established infection where the ½ life of the HIV CD4 T cell reservoir is stable and more than an average lifetime. We hypothesize that very early ARV treatment of adolescents with acute HIV infection will be associated with decreased VR size, and VR size will be significantly different between adolescents with acute, recent or established HIV infection. Individuals with low VR size may be able to attain extended periods of drug free HIV remission. Through innovative point of care screening of at risk youth N=4,500 and prospective testing of high risk seronegative youth N=1,500, we propose to identify 60 youth with established HIV and 36 with acute infection based on lab assays and Fiebig score. These youth will receive prompt potent cART and be followed for treatment response and serial assays of viral dynamics, decay and persistence of VR [(quantitative assays of HIV RNA, proviral DNA (HIV integrated/unintegrated) digital drop DNAPCR, 2LTR circles, spliced/unspliced RNA), replication competent, HIV antibody, cellular assays (HIV specific CTLs, immune activation markers)] in order to characterize biomarkers predictive of HIV remission (ARV-free undetectable HIV viremia). Viral / immune biomarkers will be compared between groups and over time for rate of VR decay. Treatment of youth who stop/ interrupt treatment will be closely followed for evidence of HIV remission and will be encouraged to restart ARV with viral rebound or clinical symptoms.