PROJECT SUMMARY With the most people ever in history currently living with HIV, stopping the HIV epidemic remains imperative. Combination antiretroviral therapy (ART) 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, and Adam Castillejo, aka the London patient, were cured of HIV following leukemia-related, MHC-matched, allogeneic hematopoietic stem cell transplantation (HSCT) from a CCR5-deficient donor. Using our allogeneic HSCT model in Mauritian cynomolgus macaque (MCM), we have demonstrated that the allogeneic immune response can potently purge the latent reservoir, but is ultimately insufficient due to susceptibility to infection. This underscores the need for CCR5 deficient donors to fully eradicate HIV in the setting of HSCT. During the course of our previous studies we have demonstrated that the CCR5-specific antibody Leronlimab can mimic a CCR5 deficient donor by occupying all available CCR5 molecules. We are now proposing to utilize Leronlimab in the setting of allogeneic HSCT to definitely demonstrate the mechanism by which CCR5 deficiency achieves HIV cure. In specific aim 1, we will measure the effect and determine the mechanism of Leronlimab administration during the peri-transplant period in SHIV-infected, ART-suppressed MCM undergoing allogeneic HSCT. In specific aim 2, we will measure if Leronlimab administered during the peri-transplant period in an HIV+ patient undergoing allogenic HSCT for cancer treatment can replicate a CCR5-deficient donor and mediate an HIV cure. This work would expand our knowledge of the mechanism of HIV cure in the setting of allogeneic HSCT and establish a new therapeutic treatment for HIV cure.