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

• Published in: PLoS pathogens Vol. 19; no. 12; p. e1011853
• Main Authors: Zhou, Yuqi, Jadlowsky, Julie, Baiduc, Caitlin, Klattenhoff, Alex W, Chen, Zhilin, Bennett, Alan D, Pumphrey, Nicholas J, Jakobsen, Bent K, Riley, James L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-12-2023; Public Library of Science (PLoS)
• Subjects: Amino acids; Antigen-presenting cells; Antigenic determinants; Antigens; Antiviral activity; Antiviral agents; Biology and Life Sciences; Caspase-3; Cell therapy; Chimeric antigen receptors; Comparative analysis; Control; Cytokines; Dosage and administration; Efavirenz; Epitopes; Flow cytometry; Genomics; HIV; HIV (Viruses); HIV infection; HIV Infections - therapy; HIV-1; Human immunodeficiency virus; Humans; Infectious diseases; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Mutation; Peptides; Prevention; Ratios; Receptors; Receptors, Antigen, T-Cell - genetics; Receptors, Chimeric Antigen - genetics; Replication; Research and Analysis Methods; Risk factors; T cell receptors; T cells; Target recognition; Virus Replication; United Kingdom
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011853

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.