Induction of interleukin-15 production by HIV-1 Nef protein: A role in theproliferation of uninfected cells

Several recent reports have provided evidence that Nef enhances human immun odeficiency virus HIV infectivity, and in vitro experiments with the nef ge ne have demonstrated the possible role of Nef in modulating immune response s. Exogenous Nef has been demonstrated to induce proliferation of normal hu man peripheral blood mononuclear cells (PBMC) and to enhance HIV-1 replicat ion. The aim of this study was to evaluate the biological mechanisms by whi ch Nef, used as exogenous protein, modulates cellular activation. We showed that exogenous Nef protein induces the proliferation of unstimulated and s uboptimally stimulated normal human PBMC, while it has no effect on the pro liferation of optimally stimulated PBMC. Moreover, the activating effect of exogenous Nef on PBMC proliferation was associated with an increase of IFN -gamma, TNF-alpha, and IL-6 production, while, surprisingly, IL-2 productio n was not affected by Nef. More importantly we showed, for the first time, that Nef exerts its activating effects on PBMC proliferation through IL-15 synthesis induction by monocyte/macrophage population. In conclusion, we fo und that exogenous Nef protein (i) induces activation of normal PBMC, incre asing their proliferative response; (ii) modulates cytokine production; (ii i) exerts its activating effects through IL-15 synthesis induction; and (iv ) exerts these effects entering monocyte/macrophages. Our results might sug gest that Nef enhances the rate of viral replication by a novel mechanism i nvolving the production of IL-15. (C) 1999 Academic Press.