Journal
ACS CHEMICAL BIOLOGY
Volume 15, Issue 8, Pages 2299-2310Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.0c00537
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Funding
- School of Pharmacy at the University of Southern California
- Pre-Doctoral Fellowship in Pharmaceutical Sciences from the American Foundation for Pharmaceutical Education
- National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [R21AI155117, R21AI140866]
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Engineering T cells and natural killer (NK) cells with anti-HIV chimeric antigen receptors (CAR) has emerged as a promising strategy to eradicate HIV-infected cells. However, current anti-HIV CARs are limited by targeting a single epitope of the HIV envelope glycoprotein gp160, which cannot counter the enormous diversity and mutability of viruses. Here, we report the development of a universal CAR-NK cell, which recognizes 2,4-dinitrophenyl (DNP) and can subsequently be redirected to target various epitopes of gp160 using DNP-conjugated antibodies as adaptor molecules. We show that this CAR-NK cell can recognize and kill mimic HIV-infected cell lines expressing subtypes B and C gp160. We additionally find that anti-gp160 antibodies targeting membrane-distal epitopes (including V1/V2, V3, and CD4bs) are more likely to activate universal CAR-NK cells against gp160(+ )target cells, compared with those targeting membrane-proximal epitopes located in the gp41 MPER. Finally, we confirm that HIV-infected primary human CD4(+) T cells can be effectively killed using the same approach. Given that numerous anti-gp160 antibodies with different antigen specificities are readily available, this modular universal CAR-NK cell platform can potentially overcome HIV diversity, thus providing a promising strategy to eradicate HIV-infected cells.
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