INTERLEUKIN-18 STIMULATES HIV TYPE-1 IN MONOCYTIC CELLS

The cytokine interleukin (IL) 18 (formerly interferon gamma-inducing f actor) induces the T helper type 1 response. In the present studies, I L-18 increased HIV type 1 (HIV-1) production from 5- to 30-fold in the chronically infected U1 monocytic cell line. Inhibition of tumor necr osis factor (TNF) activity by the addition of TNF-binding protein redu ced IL-18-stimulated HIV-1 production by 48%. In the same cultures, IL -18-induced IL-8 was inhibited by 96%. Also, a neutralizing anti-IL-6 mAb reduced IL-18-induced HIV-1 by 63%. Stimulation of U1 cells with I L-18 resulted in increased production of IL-6, and exogenous IL-6 adde d to U1 cells increased HIV-1 production 4-fold over control, A specif ic inhibitor of the p38 mitogen-activated protein kinase reduced IL-18 -induced HIV-1 by 73%, and a 50% inhibition was observed at 0.05 mu M. In the same cultures, IL-8 was inhibited by 87%. By gel-shift and sup ershift analyses, increased binding activity of the transcription fact or NF-kappa B was measured in nuclear extracts from U1 cells 1 h after exposure to IL-18, These results demonstrate induction of HTV-1 by IL -18 in a monocyte target associated with an intermediate role for TNF and IL-6, activation of p38 mitogen-activated protein kinase, and nucl ear translocation of NF-kappa B.