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Cell. 2019 Oct 31;179(4):880-894.e10. doi: 10.1016/j.cell.2019.10.002. Epub 2019 Oct 24.

Attacking Latent HIV with convertibleCAR-T Cells, a Highly Adaptable Killing Platform.

Author information

1
Gladstone Center for HIV Cure Research, Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA; Departments of Medicine and Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Xyphos Biosciences, Inc., South San Francisco, CA 94080, USA.
3
Gladstone Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Departments of Biochemistry and Biophysics and Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
5
Gladstone Center for HIV Cure Research, Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA; Gladstone Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Departments of Biochemistry and Biophysics and Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Gladstone Center for HIV Cure Research, Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA; Departments of Medicine and Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: warner.greene@gladstone.ucsf.edu.

Abstract

Current approaches to reducing the latent HIV reservoir entail first reactivating virus-containing cells to become visible to the immune system. A critical second step is killing these cells to reduce reservoir size. Endogenous cytotoxic T-lymphocytes (CTLs) may not be adequate because of cellular exhaustion and the evolution of CTL-resistant viruses. We have designed a universal CAR-T cell platform based on CTLs engineered to bind a variety of broadly neutralizing anti-HIV antibodies. We show that this platform, convertibleCAR-T cells, effectively kills HIV-infected, but not uninfected, CD4 T cells from blood, tonsil, or spleen and only when armed with anti-HIV antibodies. convertibleCAR-T cells also kill within 48 h more than half of the inducible reservoir found in blood of HIV-infected individuals on antiretroviral therapy. The modularity of convertibleCAR-T cell system, which allows multiplexing with several anti-HIV antibodies yielding greater breadth and control, makes it a promising tool for attacking the latent HIV reservoir.

KEYWORDS:

CAR-T; HIV latency; MicAbody; T cell therapy; bNAb; broadly neutralizing HIV antibodies; convertibleCAR-T; reduce-and-control; reservoir; shock-and-kill

PMID:
31668804
PMCID:
PMC6922308
[Available on 2020-10-31]
DOI:
10.1016/j.cell.2019.10.002

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