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

Abstract

Natural killer (NK) cells are innate cytolytic effectors that target HIV-infected CD4+ Tcells. 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+ Tcells, 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) Tcells demonstrate that the viral envelope is equally accessible on CD4+ Tcells and macrophages. Nonetheless, ADCC against macrophages is muted compared with ADCC against CD4+ Tcells. 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.