ENHANCEMENT OF NATURAL-KILLER AND ANTIBODY-DEPENDENT CYTOLYTIC ACTIVITIES OF THE PERIPHERAL-BLOOD MONONUCLEAR-CELLS OF HIV-INFECTED PATIENTS BY RECOMBINANT IL-15

Natural killer (NK) cells are an important subset of lymphocytes capab le of killing virus-infected target cells without prior sensitization. HIV-infected individuals show impairment of their NK cell activity. A lthough the mechanism responsible for this defect remains unclear, NK cytotoxicity of lymphocytes from these individuals can be partially re stored by interleukin (IL)-2. IL-15 is a recently discovered cytokine that shares many biologic activities with IL-2-for example, enhancemen t of NK activity. In this study, we investigated the effect of recombi nant IL-15 (rIL-15) on the NK and antibody-dependent cellular cytotoxi city (ADCC) effector activities of peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals using K562 cell line and HIV gp1 20-expressing cells. The effect of anti-IL-15 antibodies on NK activit y was also examined using PBMCs of HIV-seronegative individuals. Our r esults show that NK and ADCC activities of PBMCs in HIV-seropositive p atients were significantly lower than those of seronegative donors (p less than or equal to 0.05). However, these two activities were signif icantly enhanced when rIL-15 was added to the assay wells (p less than or equal to 0.05). Moreover, addition of saturating concentrations of neutralizing monoclonal antibodies (mAb) specific for IL-2, IL-12, or interferon (IFN)-gamma in the assays failed to inhibit IL-15-mediated enhancement of NK cell functions. Only the antibody against IL-15 abr ogated the upregulation of NK and ADCC activities mediated by IL-15, s uggesting that this cytokine enhances NK cell functions through a mech anism that is independent of the induction of other cytokines. IL-15 d id not exert any modulatory effect on the expression of CD16 or CD56 m olecules. Our results show that IL-15 can increase the NK and ADCC act ivities of the PBMCs of HIV-infected individuals in vitro. In view of its higher therapeutic index as determined using murine models, IL-15 may represent a better immunotherapeutic agent than IL-2 to restore th ese functions in HIV-seropositive patients.