ABSTRACT Hematopoietic stem cell transplantation (HSCT) is currently the only known treatment that has resulted in durable HIV-1 remission/functional cure as shown in the Berlin Patient, and most recently also in the London Patient. Both of these patients were treated for associated malignancies; significant improvements are needed in order to apply these case studies to a broader population of HIV+ individuals. Our U19 consortium is focused on enhancing the anti-HIV function of gene-edited HSPC, and safely engrafting these cells in vivo. The Nonhuman Primate (NHP) Core will play a central role in organizing all large animal studies proposed by each project in our group, with a focus on approaches that are most suitable for future trials in patients. We will work closely with Project 3/Cannon and Project 4/Kiem to adapt an optimized protocol to gene edit HSPCs, with a focus on maximizing homology directed repair (HDR). In Project 1/Scadden, Project 2/Magenta, and Project 4 Kiem, we will apply and evaluate this approach in a total of 40 NHPs. Each animal will receive autologous, HDR-modified HSPCs containing either barcoded, gene-edited CCR5 alleles (∆CCR5), or a “three for one” product containing both CD4CAR∆CCR5 and eCD4-Ig∆CCR5 HSPCs. To evaluate the efficacy of our strategy, we will model HIV infection in NHPs, using simian/human immunodeficiency virus (SHIV). In one study design, 24 animals will be transplanted with gene edited HSPCs, followed by SHIV challenge to quantify protection against virus acquisition. To model HIV persistence, 16 animals will be infected with SHIV and suppressed by antiretroviral therapy (ART) prior to HSPC transplantation. Following recovery, animals will be removed from ART, and the kinetics and magnitude of SHIV rebound will be compared to untransplanted control animals. In addition to CD4CAR∆CCR5 and eCD4-Ig∆CCR5 HSPCs, animals will also receive a nongenotoxic conditioning (NGC) regimen designed by Project 2/Magenta, and bone marrow cryogel (BMC) developed by Project 1/Scadden. These additional treatments will substantially enhance the safety and efficacy of our approach, respectively. The NHP Core will implement both of the SHIV study designs described above, produce gene edited NHP HSPC products, and provide supportive care following HSPC gene therapy and infection with SHIV. The large animal studies we direct on behalf of each project will contribute meaningfully to discussions regarding synergies between projects, and selection of the best combinations to forward to early phase clinical studies.