Development of HIV-Resistant CAR T Cells by CRISPR/Cas-Mediated CAR Integration into the CCR5 Locus.

Autor: Rothemejer FH; Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus, Denmark., Lauritsen NP; Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus, Denmark., Juhl AK; Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus, Denmark., Schleimann MH; Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus, Denmark., König S; Department of Biomedicine, Aarhus University, 8200 Aarhus, Denmark., Søgaard OS; Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus, Denmark., Bak RO; Department of Biomedicine, Aarhus University, 8200 Aarhus, Denmark.; Aarhus Institute of Advanced Studies, Aarhus University, 8200 Aarhus, Denmark., Tolstrup M; Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus, Denmark.
Jazyk: angličtina
Zdroj: Viruses [Viruses] 2023 Jan 10; Vol. 15 (1). Date of Electronic Publication: 2023 Jan 10.
DOI: 10.3390/v15010202
Abstrakt: Adoptive immunotherapy using chimeric antigen receptor (CAR) T cells has been highly successful in treating B cell malignancies and holds great potential as a curative strategy for HIV infection. Recent advances in the use of anti-HIV broadly neutralizing antibodies (bNAbs) have provided vital information for optimal antigen targeting of CAR T cells. However, CD4+ CAR T cells are susceptible to HIV infection, limiting their therapeutic potential. In the current study, we engineered HIV-resistant CAR T cells using CRISPR/Cas9-mediated integration of a CAR cassette into the CCR5 locus. We used a single chain variable fragment (scFv) of the clinically potent bNAb 10-1074 as the antigen-targeting domain in our anti-HIV CAR T cells. Our anti-HIV CAR T cells showed specific lysis of HIV-infected cells in vitro. In a PBMC humanized mouse model of HIV infection, the anti-HIV CAR T cells expanded and transiently limited HIV infection. In conclusion, this study provides proof-of-concept for developing HIV-resistant CAR T cells using CRISPR/Cas9 targeted integration.
Databáze: MEDLINE
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