Chimeric antigen receptors enable superior control of HIV replication by rapidly killing infected cells.

Autor: Zhou Y; Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America., Jadlowsky J; Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America., Baiduc C; Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America., Klattenhoff AW; Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America., Chen Z; Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America., Bennett AD; Adaptimmune Ltd, Abingdon, United Kingdom., Pumphrey NJ; Adaptimmune Ltd, Abingdon, United Kingdom., Jakobsen BK; Adaptimmune Ltd, Abingdon, United Kingdom.; Immunocore Ltd., Abingdon, United Kingdom., Riley JL; Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 Dec 15; Vol. 19 (12), pp. e1011853. Date of Electronic Publication: 2023 Dec 15 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011853
Abstrakt: Engineered T cells hold great promise to become part of an effective HIV cure strategy, but it is currently unclear how best to redirect T cells to target HIV. To gain insight, we generated engineered T cells using lentiviral vectors encoding one of three distinct HIV-specific T cell receptors (TCRs) or a previously optimized HIV-targeting chimeric antigen receptor (CAR) and compared their functional capabilities. All engineered T cells had robust, antigen-specific polyfunctional cytokine profiles when mixed with artificial antigen-presenting cells. However, only the CAR T cells could potently control HIV replication. TCR affinity enhancement did not augment HIV control but did allow TCR T cells to recognize common HIV escape variants. Interestingly, either altering Nef activity or adding additional target epitopes into the HIV genome bolstered TCR T cell anti-HIV activity, but CAR T cells remained superior in their ability to control HIV replication. To better understand why CAR T cells control HIV replication better than TCR T cells, we performed a time course to determine when HIV-specific T cells were first able to activate Caspase 3 in HIV-infected targets. We demonstrated that CAR T cells recognized and killed HIV-infected targets more rapidly than TCR T cells, which correlates with their ability to control HIV replication. These studies suggest that the speed of target recognition and killing is a key determinant of whether engineered T cell therapies will be effective against infectious diseases.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AB, NLP, and BKJ were employees of Adaptimmune when these studies were performed. Adaptimmune hold patents on TCRs described in this manuscript. JLR is an inventor of patents related to the HIV CAR therapy, which is the subject of this paper, as well as other CAR therapy products, and may be eligible to receive a select portion of royalties paid from Kite to the University of Pennsylvania. JLR is a scientific co-founder and holds equity in BlueWhale Bio.
(Copyright: © 2023 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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