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Antibody-dependent activation of natural killer (NK) cells might facilitate protective outcomes in the context of HIV exposure or infection. Antibody-dependent activation is heightened in NK cells educated by interactions between killer immunoglobulin-like receptors (KIRs) and their major histocompatibility complex class I ligands during ontogeny. Differentiated NK cells, defined as CD57+, also exhibit enhanced antibody-dependent responsiveness. Although KIRs are more frequently expressed on CD57+ NK cells, the presented data suggest education and differentiation make independent contributions to NK cell anti-HIV envelope antibody-dependent activation.