PROJECT SUMMARY With the most people ever in history currently living with HIV, stopping the HIV epidemic remains imperative. Combination antiretroviral therapy (cART) limits viral replication, but is not curative. Thus, there is an urgent need to design a functional cure via elimination of the viral reservoir. Timothy Brown, aka the Berlin Patient, remains HIV free in the absence of cART following leukemia-related, MHC-matched, allogeneic hematopoietic stem cell transplantation (HSCT) from a CCR5 deficient donor. The mechanisms underlying this functional cure are not known, but may depend on the immune conditioning regimen, graft-versus-host immunity, or a reconstituted immune system lacking CCR5. Non-human primates are the best model of HIV infection, but previous transplant studies have used autologous or MHC-mismatched allogeneic HSCT due to the complexity of non-human primate MHC. Also, no CCR deficient macaque donors exist. Thus, no studies have been able to recapitulate the transplant of Timothy Brown. We have built an allogeneic HSCT model using a novel, Mauritian cynomolgus macaque (MCM). MCM have extremely simplified genetics due to a recent bottleneck approximately 500 years ago. Furthermore, we are currently using CRISPR technology to generate CCR5 deficient donors. Therefore, we are uniquely positioned to recapitulate Timothy Brown’s transplant in a clinically relevant animal model. In specific aim 1, we will measure the impact of myeloablative chemotherapy on clearing the latent viral reservoir in autologous HSCT transplants. In specific aim 2, we will perform fully MHC-matched HSCT, measure graft-versus host immunity, and correlate it to SIV rebound in the plasma and tissues. In specific aim 3, we will use our CCR5 deficient donors to perform an allogeneic HSCT with stem cells lacking CCR5. Overall, this study will allow us to map the determinants of HIV clearance following HSCT.