Amplifying and Redirecting CMV-specific CD8 T cells to provide sustained control of HIV infection

The immune system of HIV-infected individuals is unable to eliminate latently infected cells following reactivation, resulting in the recurrence of viremia after stopping antiretroviral therapy, preventing functional cure. This necessitates lifelong ART for people with HIV (PWH). New strategies are needed to mobilize the immune system to prevent the emergence of HIV from the HIV reservoir after ART cessation. We recently developed synTacs, infusible immunostimulatory biologics consisting of dimeric Fc-domain scaffolds linking MHC molecules and virus-derived peptides (c-pMHC) capable of delivering antigen-specific TCR-signals and ligands that supply defined costimulatory signals. We demonstrated that synTacs bearing CMV-derived peptides, and anti-CD28 scFv or 4-1BBL signaling modules, stimulated vigorous and selective ex vivo and in vivo expansion of highly polyfunctional CMV-specific CD8+ T cells in PWH PBMC, which displayed potent in vivo anti-CMV activities. We also recently described the potent in vitro and in vivo anti-HIV activity of CAR-T cells that use a novel two- molecule duoCAR architecture to co-express two independent CARs, each recognizing a distinct gp120 epitope. HIV-specific T cell responses or CAR-T cell treatments fail to provide sustained control of HIV infection because of the eventual reduction or loss of their functional anti-HIV activity, even in the absence of mutational immune escape. In contrast, CMV-specific T cell responses consist of effector memory CD8 T cells that maintain their capacity for cytokine release, killing and proliferation and actually expand over time, a phenotype described as memory inflation. We hypothesize that combining the capacity of synTacs to activate and markedly expand CMV- specific CD8 T cells with novel strategies to redirect them to eliminate HIV-infected cells, would exploit the highly functional and resilient CMV-specific CD8 T cell responses to provide improved immune control of HIV infection. We propose to combine the capacity of synTacs to selectively activate and markedly expand CMV-specific CD8 T cells with potent and sustained anti-viral activity with three Specific Aims (SA) to redirect them to target HIV- infected cells. We will either convert the expanded CMV CD8 T cells into HIV-specific CAR T cells (SA 1), or anti-HIV T cells (SA 2), or modify the synTac structure to link CMV-c-pMHC, gp120-binders and costimulatory ligands, to both fully activate and direct CMV CD8 T cells to target HIV-infected cells (SA 3), thereby mobilizing an in vivo immune response that controls HIV infection, eliminates reactivated latently infected cells and provides sustained ART-free remission of HIV infection to PWH. Furthermore, we will also utilize synTacs delivering defined costimulatory signals, to extend our knowledge regarding the capacity of different costimulatory signals to generate the most potent CD8+ T cells and CAR-T cells for eliminating reactivated latently infected T cells.