IL-15, a new cytokine primarily produced by macrophages, has been shown to exhibit several functional properties shared with IL-2. Treatment of PBMC from HIV-infected patients with IL-15 resulted in an increase in NK cell cytotoxicity to levels similar to those of untreated PBMC from healthy donors. This effect is independent of several well-characterized regulatory cytokines, as it is not prevented by Abs that neutralize IFNs, TNF-alpha, IL-2, or IL-12. Enhanced cytotoxicity was accompanied by a significant increase in expression of cytotoxic granules. IL-15 enhanced the proliferative ability in both controls and HIV-seropositive in response to mitogen and recall Ags. Although the addition of IL-15 has a preventive effect on the appearance of spontaneous cell death, this effect was not seen during mitogen-induced apoptosis. The production of IL-15 by PBMC from patients in response to Staphylococcus aureus Cowan strain 1 appeared heterogeneous and was not negatively regulated by cytokines that inhibited IL-12 production. No correlation was found between in vitro HIV infection and IL-15 production, as viral infection had no effect on the ability of monocytes to produce IL-15 in response to S. aureus. Interestingly IL-15 restored the deficient production of IL-12 by PBMC from HIV+ people and had no major effect on modulating viral expression in latently infected cell lines or PBMC from naturally infected people. Taken together, these results suggest a potent immunoregulatory role of IL-15 during HIV infection.