NATURAL-KILLER-CELLS FROM HIV-1(-C CHEMOKINES AND INHIBIT HIV-1 INFECTION() PATIENTS PRODUCE C)

Human NK cells have been shown to produce cytokines (e.g., IFN-gamma a nd TNF-alpha) and the chemokine macrophage inflammatory protein (MIP)- 1 alpha following stimulation with the combination of two monokines, I L-15 plus IL-12, The C-C chemokines MIP-1 alpha, MIP-1 beta, and RANTE S have been identified as the major soluble macrophage-tropic HIV-1-su ppressive factors produced by CD8(+) T cells, which exert their action at the level of viral entry, sere, we demonstrate that monokine-activ ated NK cells, isolated from both normal and HIV-1(+) donors, produce similar amounts of MIP-1 alpha, MIP-1 beta, and RANTES protein, in vit ro. Further, supernatants of monokine-activated NK cells obtained from both normal donors and AIDS patients showed potent (routinely greater than or equal to 90%) suppressive activity against HIV-1 replication in vitro, compared with unstimulated control supernatants, NK cell sup ernatants inhibited both macrophage-tropic HIV-1(NFN-SX) and T cell-tr opic HIV-1(NL4-3) replication in vitro, but not dual-tropic HIV-1(89.6 ). Importantly, the C-C chemokines MIP-1 alpha, MIP-1 beta, and RANTES were responsible only fora fraction of the HIV-1-suppressive activity exhibited by NK cell supernatants against macrophage-tropic HIV-1, Co llectively 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 cam 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.