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ABSTRACT: Natural killer (NK) cells are a crucial component of the host innate immune system. We investigated the noncytolytic anti-human immunodeficiency virus (HIV) activity of NK cells in chronically HIV-infected immune cells. Supernatants collected from NK cell cultures (both primary NK cells and NK cell lines, YTS and NK 92) inhibited HIV activation in peripheral blood mononuclear cells (PBMCs) from HIV-infected subjects. NK supernatants (NK SN) also suppressed tumor necrosis factor (TNF)-alpha-induced HIV activation in chronically infected cell lines (U1 and ACH-2 cells). The antibody to interferon (IFN)-gamma blocked NK SN-mediated anti-HIV effect, while the antibodies to CC-chemokines had no impact on NK SN-mediated HIV inhibition in U1 and ACH-2 cells. Investigation of mechanism(s) responsible for the NK action showed that NK SN inhibited TNF-alpha-mediated activation of HIV-long-terminal repeat (LTR), and upregulated the expression of signal transducer and activator of transcription (STAT)-1 and phosphorylated P38 mitogen-activated protein kinase (MAPK). The P38 MAPK inhibitor (SB 203580) blocked NK SN-mediated HIV inhibition. These data provide compelling evidence that NK cells have a critical role in controlling HIV activation in the reservoirs.