PROJECT SUMMARY A cure for HIV requires the elimination of the latently-infected pool of host cells harboring HIV provirus, but this has proven quite difficult and remains a major obstacle in the field. Currently, several chemical latency reversing agents have been described, however, their in vivo efficacy has not been demonstrated. Thus, the need for new approaches to address this issue is urgently needed. One attractive method to combat HIV latency, would be a self-sustaining curative to endlessly surveil the host rapidly killing newly activated reservoir cells before the release of a significant amount of virus. Previously, T cells transduced to express CD4 on their surface linked to activation signaling machinery, chimeric antigen receptor (CAR) T cells, were employed to target and kill infected host cells. But there were substantial drawbacks with this approach, including a novel entry route for infection of CD8 T cells, shielding of the CD4-binding site, and lack of efficacy. Utilizing secreted high-affinity anti-HIV bnAbs, which are remarkably effective across a wide swath of HIV strains, in conjunction with superior CAR designs, we here propose to exploit both advancements to generate doubly immunotherapeutic improved CAR T cells. These pioneering studies will provide new insights into how to access and control the reservoir of latently HIV-infected cells and, in combination with ART, address the exigent goal of functional control of HIV. Upon completion of this project, we expect to have several validated CAR T cell constructs ready for future testing in SHIV non-human primate models and/or perhaps humans. Since these studies utilize autologous T cells, we expect to see very few adverse events. Moreover, if successful, life-long use of anti-retrovirals, which have been associated with toxicity, is likely to be reduced or perhaps eliminated by this approach.