Targeting PD-1 + T cells with chimeric antigen receptors to reduce the HIV reservoir
Open accessPublished version of a preprint
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.
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Cites
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- Authors
- Ermellino, L., Banga, R., Georgakis, S., Kadzioch, N. P., Procopio, F., Alcaraz-Serna, A., Alfageme-Abello, O., Porret, R., Cecchin, R., Orfanakis, M., Schelling, R., Brenna, C., Can, D.-C., Foglierini, M., Chén, O. Y., Perez, L., Fenwick, C., Perreau, M., Petrovas, C., Speck, R. F., Pantaleo, G., & Muller, Y. D.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- University of Zurich (CH)
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
- ORCID
- Ermellino, Laura
- Georgakis, Spiros
- Kadzioch, Nicole P.
- Alcaraz-Serna, Ana
- Alfageme-Abello, Oscar
- Porret, Raphaël
- Cecchin, Rebecca
- Orfanakis, Michail
- Schelling, Rachel
- Brenna, Cloé
- Can, Duy-Cat
- Foglierini, Mathilde
- Chén, Oliver Y.
- Perez, Laurent
- Fenwick, Craig
- Perreau, Matthieu
- Petrovas, Constantinos
- Speck, Roberto F.
- Pantaleo, Giuseppe
- Muller, Yannick D.
- Venue
- Science Advances
- Published
- 2026-04-24
- Volume
- 12
- Issue
- 17
- Pages
- eaeb7602-eaeb7602
- ISSN
- 2375-2548 (ISSN-L)
- OpenAlex
- W4414303580
- Cited by
- 0
- References
- 6
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Science Advances (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Gabriella Giorgi-Cavaglieri Foundation
- Swiss Vaccine Institute
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- HIV reservoir, PD-1, chimeric antigen receptor T cells, 4-1BB, trogocytosis, T cell depletion, cell markers, humanized mice, virus protection, splenic white pulp
- MeSH terms
- Receptors, Chimeric Antigen, Animals, Humans, T-Lymphocytes, HIV-1, HIV Infections, Immunotherapy, Adoptive, Mice, Programmed Cell Death 1 Receptor
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