ADAM17 blockade restores natural killer cell antibody-dependent cytotoxicity against human immunodeficiency virus-1

Natural killer (NK) cells are critical innate effector cells against human immunodeficiency virus type 1 (HIV-1) transmission and pathogenesis. Among the diverse NK cell functions, antibody-dependent cellular cytotoxicity (ADCC) is the most critical for HIV-1 control. Nevertheless, multiple reports have demonstrated dysfunctional NK cell activity in people living with HIV-1 (PLWH), including impaired ADCC. As a putative mechanism, CD16 signaling activation in PLWH is perturbed via ADAM17-mediated CD16 downregulation, and ADAM17 blockade can reverse CD16 downregulation in PLWH NK cells. However, the link between elevated ADAM17 function and diminished HIV-1-specific NK cell ADCC has remained unclear. Thus, to fill this knowledge gap, we tested whether ADAM17 perturbation can restore HIV-1-specific NK cell ADCC. We demonstrated that inhibition of ADAM17 can restore HIV-1-specific ADCC by recovering surface CD16 expression. Furthermore, we observed that PLWH NK cells experience impaired ADCC associated with ADAM17 elevation. Altogether, we found that ADAM17 blockade can restore impaired NK cell ADCC against HIV-1, and this approach could be applied to further advance NK cell-based immunotherapeutics toward an HIV-1 cure. These findings establish ADAM17 as a tractable checkpoint to enhance Fc‑effector responses and support the integration of ADAM17 targeting into NK‑cell-based HIV cure strategies.