PROJECT SUMMARY With 36 million people currently living with HIV worldwide and no vaccine currently available, developing a pre- exposure prophylactic (PREP) HIV regimen that protects against sexual transmission remains a top global health priority. Recently, a CCR5 blocking monoclonal antibody, Leronlimab, has shown exceptional safety, tolerability, and anti-HIV activity in multiple clinical trials. Given that sexual transmission of HIV is almost exclusively mediated by CCR5-tropic variants, Leronlimab may be extremely effective as a PREP reagent. To test this hypothesis, we will test the ability of bi-weekly dosed Leronlimab to prevent mucosal acquisition of SHIV in macaques. In specific aim 1, we will administer Leronlimab and sham every two weeks and challenge macaques weekly with low dose SHIV intra-rectally. In specific aim 2, we will measure the CCR5 occupancy in blood and rectal tissues of treated animals. These studies will lay the foundation for testing Leronlimab clinically as PREP in individuals at high-risk of acquiring HIV.