PROJECT SUMMARY The 2015 UNAIDS report estimates that over 35 million people are infected with HIV. Despite the lack of a sterilizing cure, antiretroviral drug therapies (ART) effectively suppress viral replication in infected individuals. However, only 17 million infected individuals have access to ART. Additionally, ART is a life-long therapy that requires daily administration and is associated with a range of unwanted side effects. Broadly neutralizing antibodies (bNAbs) may be able to supplement or replace ART. Several such antibodies have already shown promise in human clinical trials, where a single dose can decrease viremia in HIV-1 infected individuals. However, viral rebound occurs rapidly during treatment as the bNAb concentration decreases and resistant variants are selected. Adeno-associated virus (AAV) vectors can express bNAbs for years at concentrations capable of limiting viral evolution and maintaining viral suppression. However, we and other groups have shown the emergence of anti-drug antibodies (ADA) to expressed bNAbs that can limit their expression. In this K99/R00 proposal, I will address three key questions associated with the use of AAV-delivered bNAbs in a functional cure. 1) Which bNAbs have biophysical and neutralization properties consistent with suppressing an established infection? 2) Can vector and AAV capsid optimization increase bNAb expression and help limit the host ADA response? 3) Can AAV-delivered bNAbs suppress an established SHIV infection in rhesus macaques, obviating the need for ART? By answering these questions, we will determine how best to use AAV vectors to treat an AAV infection, and provide insight for investigators using AAV in other clinical contexts. My research with AAV and HIV-1 systems and my development of non-human primate projects as a Ruth L. Kirschstein Fellow have provided me with the training necessary to complete these aims. TSRI provides an outstanding research environment for collaborative science, especially in the HIV field. Moreover, I will attend courses offered at TSRI and Cold Spring Harbor that will provide further training on becoming an independent investigator. My mentor, Dr. Farzan, along with my Scientific Advisory Committee consisting of Drs. Ron Desrosiers, Susana Valente and Hyeryun Choe, are committed to providing me with an excellent training in developing my research goals and improving my grant writing skills for future R01 submissions. The skills I acquire during the training phase will serve as a foundation for my own research program during the independent phase, with the specific goals of developing new gene-therapy vectors and applying these vectors to human diseases.