HIV-infected macrophages resist efficient NK cell-mediated killing while preserving inflammatory cytokine responses

Natural killer (NK) cells are innate cytolytic effectors that target HIV-infected CD4⁺ T cells. In conjunction with antibodies recognizing the HIV envelope, NK cells also eliminate HIV-infected targets through antibody-dependent cellular cytotoxicity (ADCC). However, how these NK cell functions impact infected macrophages is less understood. We show that HIV-infected macrophages resist NK cell-mediated killing. Compared with HIV-infected CD4⁺ T cells, initial innate NK cell interactions with HIV-infected macrophages skew the response toward cytokine production, rather than release of cytolytic contents, causing inefficient elimination of infected macrophages. Studies with chimeric antigen receptor (CAR) T cells demonstrate that the viral envelope is equally accessible on CD4⁺ T cells and macrophages. Nonetheless, ADCC against macrophages is muted compared with ADCC against CD4⁺ T cells. Thus, HIV-infected macrophages employ mechanisms to evade immediate cytolytic NK cell function while preserving inflammatory cytokine responses. These findings emphasize the importance of eliminating infected macrophages for HIV cure efforts.