Targeting PD-1 + T cells with chimeric antigen receptors to reduce the HIV reservoir
- Laura Ermellino
- Riddhima Banga
- Spiros Georgakis
- Nicole P. Kadzioch
- Francesco Procopio
- Ana Alcaraz-Serna
- Oscar Alfageme-Abello
- Raphaël Porret
- Rebecca Cecchin
- Michail Orfanakis
- Rachel Schelling
- Cloé Brenna
- Duy-Cat Can
- Mathilde Foglierini
- Oliver Y. Chén
- Laurent Perez
- Craig Fenwick
- Matthieu Perreau
- Constantinos Petrovas
- Roberto F. Speck
- Giuseppe Pantaleo
- Yannick D. Muller
2026-04-24
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.