Engineering HIV-resistant CAR T cells for a functional HIV cure

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Project Summary/Abstract The human immunodeficiency virus (HIV) promptly subverts the host cellular immune response through rapid viral escape, as well as high antigen loads leading to chronic immune activation, T cell exhaustion, and immune dysfunction. The advent of potent antiretroviral therapy (ART) capable of fully suppressing viral replication has drastically reduced the morbidity and mortality of HIV infection. However, ART must be taken indefinitely as HIV persists in long-lived stable reservoirs and thus presents a significant public health burden that can only be alleviated with a preventative vaccine and more potent cure approaches. Given that HIV effectively evades the cellular immune response, and the latent HIV reservoir is preferentially seeded with virus harboring relevant cytotoxic T lymphocyte (CTL)-escape mutations, genetic engineering modalities may offer a potent alternative to intrinsic immunity. Chimeric antigen receptor (CAR) T cells have shown impressive efficacy in eliminating blood cell cancers in the clinic, and CAR T cells re-engineered to target HIV using the CD4 ectodomain (CD4-CAR T) represent a potent escape-resistant cellular therapy demonstrated to have enhanced cytotoxic function over traditional cytotoxic T lymphocytes. We have recently described the creation of a significantly enhanced dual costimulatory domain CAR T cell product (Dual CARs), which significantly outperformed 3rd generation CAR T cells in vivo. Importantly, these studies identified at least two additional hurdles to CD4-CAR T cell efficacy in vivo, which likely informs translation to the clinic. First, CD4-CAR T cells rapidly upregulate multiple inhibitory receptors, express transcription factors associated with exhaustion, and display attenuated function ex vivo. Secondly, our studies definitively show that suppression of plasma viral load requires protection of the CAR T cell product from HIV infection. This proposal seeks to address these deficits in CD4-ectodomain CAR T cell therapy by 1) defining the mechanism(s) by which chronic HIV exposure attenuates T cell function, and 2) developing novel combinatorial strategies to fully protect CD4-CAR T cells from HIV infection, with the ultimate goal of creating a T cell immunotherapy exhibiting enhanced efficacy in the clinic.