ProjectSummary TheabsenceofacureforHIV-1afterantiretroviraltherapyimpartsmultipleburdenstotheinfectedindividual (stigma, criminalization, life-long therapy), US society (continued infections, internal health care costs, PEPFAR), industry (pricing versus access, capacity for world-wide drug production), and global resource governance (UNAIDS, AIDS orphans, Global Fund, effects of declining economy on country/region HIV therapyprograms,etc.)justifyingafocusedinvestmentinidentifyingnovelstrategiestoachieveacureand/or stable remission after HIV infection. The BEAT-HIV Delaney Collaboratory to cure HIV-1 infection by combination immunotherapy has three central objectives. First, identify the best approach to target immunotherapy against replication competent reservoirs by defining the relationship between plasma and tissueclonalexpansion,characterizeintegrationsiteswithinbloodandtissue,anddeterminehowtomaximize viral reactivation of distinct reservoir compartments. Second, test clinical strategy combining IFN-? immunotherapy to activate intrinsic/innate responses and ADCC with broadly neutralizing anti-HIV antibodies (both strategies shown to have an effect in humans when used singly);? advance preclinical studies on IFN- alpha response, ex vivo combinations with added T-cell-mediated strategies, and develop innovative DNA vaccine delivery systems for sustaining neutralizing antibodies in vivo. Third, test clinical strategy that combines two gene therapy vectors to intrinsically protect HIV-specific killer cells by a ?CCR5 zinc nuclease given together with a CAR delivering HIV-specificity to CD8 T-cells;? advance the preclinical humanized mice platformtotestnovelcombinationsofimmunotherapy(with/withoutnoveldelivery)whenadministeredjointlyor insequencewiththeobjectivetorecruitmaximalintrinsic,innate,and/oradaptiveanti-HIVeffects.Objectives are supported by four support teams addressing Clinical, HIV reservoir measures, HIV evasion analysis, and BiostatisticsandDataManagement.Communityengagementtakesadvantageofa20+yearrelationshipwith the local HIV community, CFAR, and ACTG activity ensuring partnership with target populations. Central administration of resources will ensure maintenance of high impact milestones, study team communications, and yearly goal-oriented resource allocation and/or redistribution as informed by an executive committee, externaladvisoryboard,andNIHprogram.Asagroup,webringdiverseexpertiseandinnovationrepresenting the first time that distinct immunotherapy strategies with initial promising results in human trials focused on intrinsic/innate,humoralandadaptivearmsoftheimmuneresponseareactivelyjoinedtoadvanceanHIVcure and/orremissionunderasinglecommonmulti-investigator,multi-industryteam.Theentireteamiscommitted toadvancethebestoutcomesfromourcollectiveefforttoultimatelydevelopastrategytoeradicateHIV.