Natural killer cells from HIV-1⁺ patients produce C-C chemokines and inhibit HIV-1 infection

Human NK cells have been shown to produce cytokines (e.g., IFN-γ and TNF-α) and the chemokine macrophage inflammatory protein (MIP)-1α following stimulation with the combination of two monokines, IL-15 plus IL-12. The C-C chemokines MIP-1α, MIP-1β, and RANTES have been identified as the major soluble macrophage-tropic HIV-1-suppressive factors produced by CD8⁺ T cells, which exert their action at the level of viral entry. Here, we demonstrate that monokine-activated NK cells, isolated from both normal and HIV-1⁺ donors, produce similar amounts of MIP-1α, MIP-1β, and RANTES protein, in vitro. Further, supernatants of monokine-activated NK cells obtained from both normal donors and AIDS patients showed potent (routinely ≥90%) suppressive activity against HIV-1 replication in vitro, compared with unstimulated control supernatants. NK cell supernatants inhibited both macrophage-tropic HIV-1(NFN-SX) and T cell-tropic HIV-1(NL4-3) replication in vitro, but not dual-tropic HIV-1_89.6. Importantly, the C-C chemokines MIP-1α, MIP-1β, and RANTES were responsible only for a fraction of the HIV- 1-suppressive activity exhibited by NK cell supernatants against macrophage- tropic HIV-1. Collectively these data indicate that NK cells from normal and HIV-1⁺ donors produce C-C chemokines and other unidentified factors that can inhibit both macrophage- and T cell-tropic HIV-1 replication in vitro. Since NK cells can be expanded in patients with HIV-1, AIDS, and AIDS malignancy in vivo, this cell type may have an important role in the in vivo regulation of HIV-1 infection.