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Sci Transl Med. 2019 Aug 7;11(504). pii: eaav5685. doi: 10.1126/scitranslmed.aav5685.

Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model.

Author information

1
Lentigen, a Miltenyi Biotec Company, Gaithersburg, MD 20878, USA.
2
Department of Microbiology and Immunology and Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3
Protein Interactions Section, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
4
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
5
Birmingham Veterans Affairs Medical Center, Research Service, Birmingham, AL 35294, USA.
6
Center for Antibody Therapeutics, University of Pittsburgh, Pittsburgh, PA 15261, USA. boro.dropulic@lentigen.com harris.goldstein@einstein.yu.edu dsd116@pitt.edu.
7
Department of Microbiology and Immunology and Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. boro.dropulic@lentigen.com harris.goldstein@einstein.yu.edu dsd116@pitt.edu.
8
Lentigen, a Miltenyi Biotec Company, Gaithersburg, MD 20878, USA. boro.dropulic@lentigen.com harris.goldstein@einstein.yu.edu dsd116@pitt.edu.

Abstract

Adoptive immunotherapy using chimeric antigen receptor-modified T cells (CAR-T) has made substantial contributions to the treatment of certain B cell malignancies. Such treatment modalities could potentially obviate the need for long-term antiretroviral drug therapy in HIV/AIDS. Here, we report the development of HIV-1-based lentiviral vectors that encode CARs targeting multiple highly conserved sites on the HIV-1 envelope glycoprotein using a two-molecule CAR architecture, termed duoCAR. We show that transduction with lentiviral vectors encoding multispecific anti-HIV duoCARs confer primary T cells with the capacity to potently reduce cellular HIV infection by up to 99% in vitro and >97% in vivo. T cells are the targets of HIV infection, but the transduced T cells are protected from genetically diverse HIV-1 strains. The CAR-T cells also potently eliminated PBMCs infected with broadly neutralizing antibody-resistant HIV strains, including VRC01/3BNC117-resistant HIV-1. Furthermore, multispecific anti-HIV duoCAR-T cells demonstrated long-term control of HIV infection in vivo and prevented the loss of CD4+ T cells during HIV infection using a humanized NSG mouse model of intrasplenic HIV infection. These data suggest that multispecific anti-HIV duoCAR-T cells could be an effective approach for the treatment of patients with HIV-1 infection.

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