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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. We confirmed the ability of once-weekly administered Leronlimab to protect macaques from rectal transmission of CCR5-tropic SHIV. However, a once-quarterly at home formulation would dramatically increase patient adherence. To this end we will develop a novel formulation of long-acting Leronlimab that can be administered at home in a low volume able to provide coverage for three months. In specific aim 1, we will determine the pK and receptor occupancy of this new Leronlimab formulation in blood and tissue sites of sexual transmission. In specific aim 2, we will determine the length of time a single injection at the clinical dose can protect both male and female macaques against rectal transmission. In specific aim 3, we will determine the length of time a single injection of the clinical dose can protect against vaginal transmission in cycling female macaques. These studies will determine the optimal clinical dosing of long-acting Leronlimab and lay the foundation for testing long-acting Leronlimab clinically as PREP in individuals at high-risk of acquiring HIV via sexual transmission.