A Universal CAR‐NK Cell Targeting Various Epitopes of HIV‐1 gp160

Abstract

Just like cancer cells that express cell‐surface tumor antigens, HIV‐infected cells express the envelope glycoprotein gp160 upon viral budding. Hence, engineering T cells and natural killer (NK) cells with anti‐gp160 chimeric antigen receptors (CAR) has emerged as a promising strategy to eradicate HIV‐infected cells. However, current CARs are limited by targeting a single epitope on gp160, which cannot counter the enormous HIV diversity. Here, we report the development of a universal CAR‐NK cell, which recognizes 2,4‐dinitrophenyl (DNP). This anti‐DNP CAR‐NK cell can be redirected to target various epitopes of the HIV envelope using DNP‐conjugated anti‐gp160 antibodies as adaptor molecules. We have shown that this CAR‐NK cell can recognize and kill mimic HIV‐infected cell lines expressing HIV‐1 subtypes B and C gp160. We additionally found that anti‐gp160 antibodies targeting membrane‐distal epitopes were more likely to activate universal CAR‐NK cells compared with those targeting membrane‐proximal epitopes. Moreover, we demonstrated that the universal CAR‐NK cells exhibited similar efficacy to the conventional CAR‐NK cells in targeting gp160‐expressing cells. Given that numerous anti‐gp160 antibodies are readily available, this universal CAR‐NK cell can potentially be used to overcome HIV diversity and to eradicate HIV‐infected cells.Support or Funding InformationThis study is supported by a startup fund from University of Southern California School of Pharmacy (J.X.) and a Pre‐Doctoral Fellowship in Pharmaceutical Sciences from the American Foundation for Pharmaceutical Education (R.M.L.).Our proof‐of‐concept study demonstrates that we can direct universal CAR‐NK cells with DNP‐labeled broadly neutralizing antibodies to target and kill multiple variants of HIV‐infected cells. This strategy can help overcome HIV‐1 diversity and enhance eradication of infected cells, which is essential to finding an ultimate universal cure to HIV.Figure 1