PROJECT SUMMARY Despite enormous strides made in HIV treatment since the epidemic began 40 years ago, in 2020 ~38 million people globally were living which HIV, and ~1.5 million people are newly infected with HIV every year1. Combination antiretroviral therapy (cART) effectively suppresses HIV replication to virtually undetectable levels in most HIV infected patients and dramatically reduces the incidence of AIDS. Today however, an estimated 73% of people living with HIV have access to cART leaving ~10 million people without access to treatment.1 It is therefore imperative to increase access to cART and implement therapies that improve adherence and efficacy. New drug combinations have reduced to one per day the number of pills needed to be taken to effectively control HIV greatly facilitating treatment. However, as with other chronic conditions, adherence to daily medications remains a challenge for many individuals living with HIV due to structural, behavioral, and social barriers2-5. Non- adherence to treatment has significant consequences including the emergence of drug-resistance and the potential loss of therapeutic effectiveness6-8. As such, alternative approaches are being explored to decrease the burden of daily pill administration, including long-acting injectable, oral, and implantable products9-15. The fundamental hypothesis on which our program is based is that eliminating or reducing the impact of individual adherence could increase the efficacy of HIV treatment and prevention strategies. In this R01 grant and building on our existing data, we propose a comprehensive evaluation of a biodegradable and highly tunable polymeric solid implant (PSI) that offers durable and sustained HIV viral suppression, increased user compliance, and the ability to be removed in case of unanticipated adverse events or allergic reaction. We will achieve this goal by developing an ultra-long-acting biodegradable PSI using a novel engineering process to generate small size implants (1-4 cm long) with high drug content (up to 85 wt%). We propose a comprehensive evaluation of this novel drug delivery approach using modeling efforts to validate an in vitro tool to guide formulation development and a highly relevant macaque model of infection with RT-SHIV as an invaluable preclinical tool to assess the efficacy of the PSI to maintain virus suppression. This cutting-edge combined approach will be utilized to evaluate the scientific premise of our proposal in mice and macaques to investigate the safety and efficacy of a unique and highly innovative ultra-long-acting PSI technology.