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 an immune system that can resist HIV-1 infection, control viral replication below the limit of detection and persist at high functional competency in the absence of ART. We are currently performing a Phase I clinical trial that is infusing 10 billion T cells that have been made resistant to HIV infection and can recognize HIV infected via a chimeric antigen receptor (CAR) into HIV infected individuals. 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 HIV-specific T cells that have improved function and persistence (Project 1, John Wherry). This project will use well-characterized animal models to search for factors or pathways that augment T cell function and persistence to chronic infection. 2) Modeling HIV CAR T cell trafficking and persistence in Non-Human Primates (Project 2, Hans-Peter Kiem, Chris Peterson and Mike Betts). This project seeks to understand how CAR T cells traffic throughout the body and explores ways to alter this trafficking to favor HIV clearance. Additionally, the ability of HIV CAR T cells to become tissue resident memory T cells is explored. 3) Modeling combination immunotherapy for HIV Cure in a mouse models (Project 3, Jim Riley and Todd Allen). Here, we will explore how a wide array of immunotherapy approaches synergize to promote T cell control of HIV replication.4) Clinical trials engine to develop an HIV Cure study to test engineered T cells (Project 4, Usman Azam, Pablo Tebas and Jim Hoxie). This industry led project will develop an improved process to manufacture engineered T cells from HIV infected individuals and then take the most promising approaches developed by Projects 1-3 to conduct a Phase I clinical trial. The Program is supported by 2 Cores: Core A is the administrative Core (PI, Jim Riley); Core B is the Genome Engineering Core (PI, Rick Bushman). In addition, our Program takes advantage of existing School of Medicine and CFAR Cores to promote cost sharing and avoid duplication of resources.

Overall – Project Narrative Current HIV-1 therapy (HAART) can control but not cure HIV-1 infection. The overarching scientific theme of this Program is to discover and apply novel approaches and state-of-the-art technologies to protect, direct, and sustain anti-HIV T cell responses that can obviate the need for lifelong HAART in HIV-infected patients.