Induction of autophagy to enhance CAR-T cells in HIV cure approaches

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ABSTRACT Chimeric Antigen Receptor (CAR) T-cells have emerged as a promising immunotherapy in controlling HIV-1 infection. However, CAR-T cells are also subject to immune dysfunction/exhaustion mediated by persistent inflammation during chronic HIV infection. Strategies to prevent exhaustion/restore functions of anti- HIV CAR-T cell are critical for ultimately achieving HIV functional cure. Our preliminary studies have showed that autophagy induction can improve mitochondria function and promote CAR-T cell cytotoxic T lymphocyte activity in vitro. Importantly, we found that induction of autophagy can prevent excessive IFN-I signaling and in vivo treatment with autophagy inducer rapamycin in chronically HIV infected humanized mice can decrease inflammation, restore exhausted anti-viral T cell function, and reduce viral loads. In addition, we found that autophagy inducers such as rapamycin allow efficient HIV-1 latency reversal by PKC activator bryostatin-1 while reducing T cell activation associated immune toxicity. Therefore, we hypothesize that autophagy induction can enhance ‘kick and kill’ HIV cure approaches by improving the survival, persistence and function of anti-HIV CAR-T cells and facilitating effective and safe latency reversal by PKC modulators. We will utilize our well-established humanized mouse model engineered with anti-HIV CD4CAR T cells to investigate the therapeutic potentials of autophagy induction for HIV ‘kick and kill’ cure approaches. Our study will also provide mechanistic insights into the development of immune exhaustion and autophagy’s regulation of CAR-T cell function and will thus have a wide impact beyond HIV cure research.