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

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. SummaryT cells can be redirected against cellular rather than viral-specific biomarkers to reduce the HIV reservoir.