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September 18, 2025Open Access

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

Key Points

CAR-T cells targeting PD-1 successfully reduced the HIV reservoir in humanized mice, enhancing treatment potential.
T-cells with anti-PD-1 CARs persisted for 70 days, correlating with improved viral protection and lymphoid disruption.
Two second-generation CARs were designed, demonstrating varied effects on T-cell sensitivity and effector functions.
Findings indicate a promising new direction for long-term HIV management by depleting specific T-cell subpopulations.

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, 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 signalling 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. Altogether, our results open new strategic avenues for reducing the HIV reservoir as we demonstrate the feasibility of depleting specific T-cell subpopulations.

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