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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\u2013PD-1 monoclonal antibody. The CAR avidity modulated T cell sensitivity, trogocytosis, and effector functions, independently of the PD-1 signaling domain. Both anti\u2013PD-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.<\/jats:p>","DOI":"10.1126\/sciadv.aeb7602","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T17:58:32Z","timestamp":1777053512000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Targeting PD-1\n                    <sup>+<\/sup>\n                    T cells with chimeric antigen receptors to reduce the HIV reservoir"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3378-1785","authenticated-orcid":true,"given":"Laura","family":"Ermellino","sequence":"first","affiliation":[{"name":"Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, 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