ABSTRACT. Despite advances in long-term antiretroviral therapy, people living with HIV (PLWH) exhibit residual viral replication and chronic inflammation that can drive a range of clinical co-morbidities. At the same time, efforts to develop a vaccine that could prevent, control, or eliminate HIV have not yet been successful. To bypass this problem, recent advances in CRISPR gene editing offer the possibility of engineering B cells directly, to secrete custom antibodies such as broadly neutralizing antibodies (bnAbs) that control HIV. As a living drug, engineered B cells could act as sensors, responding to HIV replication or vaccination, and secreting bnAbs that could reach therapeutic levels. In addition, B cells play critical roles integrating the innate and adaptive immune systems through antibody effector functions, presentation of antigens on both HLA class I and II, and by providing costimulatory signals to T cells. However, despite the potential of engineered B cells to form a novel HIV cell therapy, a potential barrier to their development is the suboptimal function of B cells in PLWH, which includes defects in T cell help. A major goal of this project is to develop an approach to provide the necessary T cell help and produce bnAb-engineered B cells that would be functional in PLWH. In Aim 1, we will design a series of synthetic protein signaling molecules that engage B cell circuits induced by T helper cells, and screen their function in reporter cell lines. In Aim 2, we will examine the ability of these molecules to drive B cell functions in primary human B cells and tonsil organoid models of vaccination. Finally, in Aim 3, we will examine the ability of engineered B cells to respond to and control HIV in a series of in vitro and in vivo models. This project encompasses cutting edge concepts and tools of cell and gene therapy. The lab and environment I have selected for this fellowship has both the facilities and expertise to fully support me in this endeavor. In addition, USC’s clinical cell therapy program is supported by both a cGMP facility and a CIRM-funded Alpha clinic, with training programs in cell therapy and expertise to help. The project also needs access to materials from PLWH, waste tonsil samples and mouse facilities suitable for HIV humanized mice work, which are all available in this environment. I will also be afforded opportunities for training in a world-class clinical environment with mentors who understand the challenges and immense opportunities afforded by a career as a physician-scientist. My training plan integrates both clinical and research experiences throughout the different phases of the MD/PhD program, to ensure that I gain the skills necessary to become a physician scientist with expertise in gene and cell therapy, poised to use these new types of medicine in my own clinical practice and future research.