Targeting PD-1+ T-cells with Chimeric Antigen Receptors to reduce the HIV Reservoir

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Rachel Schelling, Matthieu Perreau, Spiros Georgakis, Giuseppe Pantaleo, Ana Alcaraz-Serna, Duy-Cat Can, Oliver Chén, Constantinos Petrovas, Laura Ermellino, Riddhima Banga, Cloé Brenna, Craig Fenwick, Raphaël Porret, Mathilde Foglierini, Laurent Perez, Oscar Alfageme-Abello, Francesco Procopio, Michail Orfanakis, Roberto Federico Speck, Yannick D Muller et al. (2 additional authors not shown)

Published: 24 Apr 2026, Last Modified: 05 May 2026Science AdvancesEveryoneRevisionsCC BY-SA 4.0
Abstract: The unique ability of chimeric antigen receptor (CAR) T cells to infiltrate tissues is revolutionizing our perspectives for tackling severe, refractory and otherwise untreatable diseases. In HIV, CAR-T cells have been designed to target viral biomarkers, with limited success so far. Here, we investigated the possibility of redirecting CAR-T cells against a cellular biomarker of the HIV reservoir, the programmed cell death protein 1 (PD-1). We designed two second-generation 4-1BB-CARs using the scFv of either a blocking (bPD1-CAR) or a nonblocking (nbPD1-CAR) anti–PD-1 monoclonal antibody. The CAR avidity modulated T cell sensitivity, trogocytosis, and effector functions, independently of the PD-1 signaling domain. Both anti–PD-1 CAR-T cells could persist for 70 days in HIV-infected humanized mice, correlating with viral protection and a disruption of the lymphoid architecture in the white pulp of the spleen. Together, our results open strategic avenues for reducing the HIV reservoir by demonstrating the feasibility of depleting specific T cell subpopulations.