Immunoengineering Durable Control of HIV Replication - Despite anti-retroviral therapies (ART), HIV-1 continues to cause a considerable medical and economic burden, and there continues to be a pressing need for an HIV-1 cure. The goal of this Program is to generate a chimeric antigen receptor (CAR) approach that can control viral replication below the limit of detection and eliminate the viral reservoir. We recently completed a Phase I clinical trial that infused HIV resistant, HIV specific CAR T cells (CARTs) in people with HIV (PWH) in which 50% of the individuals showed post rebound control of HIV replication. A major goal of this consortium to develop strategies that improve the effector function, trafficking, and persistence of these T cells. The elements of our proposal are: 1) Engineering viral- specific T cells with improved function and persistence (Project 1, John Wherry). This project will use well- characterized models to search for factors or pathways that augment CAR T cell function and persistence to chronic infection. 2) In vivo targeting of T cells to enable an HIV cure (Project 2, Mike Betts and Drew Weissman). This project seeks to develop mRNA-LNP strategy to deliver HIV-specific CARs to effector T cells and supply the trafficking information to move these cells in the lymph tissue where HIV hides. 3) Engineering CAR T cells to provide a durable control of HIV replication (Project 3, Jim Riley). Project 3 seeks build upon the success of HIV CARTs in the clinic by increasing their sensitivity, function, and persistence. 4) Multiplex gene editing in CAR T cells and hematopoietic stem cells to enable an HIV cure (Project 4 Saar Gill and Hans- Peter Kiem). In this project we will implement a genetically engineered cell therapy platform to eradicate the cellular HIV reservoir using the power of chimeric antigen receptor T cells. The CART cells are redirected against a pan-leukocyte antigen, and coupled with an autologous stem cell transplant that is resistant to HIV as well as to the CART cells. Three industry partners (Gilead Sciences, Synthekine, and Acuitas Therapeutics) will provide proprietary reagents and know-how to assist investigators develop these HIV cure strategies and if appropriate help them perform Phase I testing, and eventually commercialize this strategy so it can be available to PWH. The Program is supported by 3 Cores: Core A is the administrative Core (PI, Jim Riley); Core B is the Genome Engineering Core (PIs, Rick Bushman, Junwei Shi, and Rahul Kohli); and NHP Core (PIs Mirko Paiardini, and Hans-Peter Kiem). In addition, our Program takes advantage of existing School of Medicine and CFAR Cores to promote cost sharing and avoid duplication of resources.
