Optimizing Intracellular Signaling Domains for CAR NK Cells in HIV Immunotherapy: a Comprehensive Review

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• NK cells are key effectors of antiviral responses that become dysregulated during HIV infection. • CAR strategies can redirect T cell and NK cell functions towards HIV-infected cells. • CAR T cell strategies applied in NK cells are sub-optimal due to differences in signal transduction. • Understanding these differences in NK and T cell signaling may enhance NK-specific CAR design. • NK and T cell signal transduction are summarized and novel NK-specific CAR strategies are discussed.

 Natural killer (NK) cells are innate immune lymphocytes with a key role in host defense against HIV infection. Recent advances in chimeric antigen receptors (CARs) have made NK cells a prime target for expressing recombinant receptors capable of redirecting NK cytotoxic functions towards HIV-infected cells. In this review, we discuss the role of NK cells in HIV and the mechanisms of actions of HIV-targeting CAR strategies. Furthermore, we also review NK cells signal transduction and its application to CAR NK cell strategies to develop new combinations of CAR intracellular domains and to improve CAR NK signaling and cytotoxic functions.

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