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

Kim Anthony-Gonda, Ariola Bardhi, Alex Ray, Nina Flerin, Mengyan Li, Weizao Chen, Christina Ochsenbauer, John C. Kappes, Winfried Krueger, Andrew Worden, Dina Schneider, Zhongyu Zhu, Rimas Orentas, Dimiter S. Dimitrov, Harris Goldstein, Boro Dropulić

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbereaav5685
JournalScience translational medicine
Volume11
Issue number504
DOIs
StatePublished - Aug 7 2019

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HIV Infections
Antiviral Agents
HIV-1
HIV
T-Lymphocytes
T-Cell Antigen Receptor
Adoptive Immunotherapy
Neutralizing Antibodies
In Vitro Techniques
Glycoproteins
Acquired Immunodeficiency Syndrome
B-Lymphocytes
Therapeutics
Drug Therapy
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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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. / Anthony-Gonda, Kim; Bardhi, Ariola; Ray, Alex; Flerin, Nina; Li, Mengyan; Chen, Weizao; Ochsenbauer, Christina; Kappes, John C.; Krueger, Winfried; Worden, Andrew; Schneider, Dina; Zhu, Zhongyu; Orentas, Rimas; Dimitrov, Dimiter S.; Goldstein, Harris; Dropulić, Boro.

In: Science translational medicine, Vol. 11, No. 504, eaav5685, 07.08.2019.

Research output: Contribution to journalArticle

Anthony-Gonda, K, Bardhi, A, Ray, A, Flerin, N, Li, M, Chen, W, Ochsenbauer, C, Kappes, JC, Krueger, W, Worden, A, Schneider, D, Zhu, Z, Orentas, R, Dimitrov, DS, Goldstein, H & Dropulić, B 2019, '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', Science translational medicine, vol. 11, no. 504, eaav5685. https://doi.org/10.1126/scitranslmed.aav5685
Anthony-Gonda, Kim ; Bardhi, Ariola ; Ray, Alex ; Flerin, Nina ; Li, Mengyan ; Chen, Weizao ; Ochsenbauer, Christina ; Kappes, John C. ; Krueger, Winfried ; Worden, Andrew ; Schneider, Dina ; Zhu, Zhongyu ; Orentas, Rimas ; Dimitrov, Dimiter S. ; Goldstein, Harris ; Dropulić, Boro. / 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. In: Science translational medicine. 2019 ; Vol. 11, No. 504.
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