INTERLEUKIN-1 INDUCES HIV-1 EXPRESSION IN CHRONICALLY INFECTED U1 CELLS - BLOCKADE BY INTERLEUKIN-1 RECEPTOR ANTAGONIST AND TUMOR-NECROSIS-FACTOR BINDING-PROTEIN TYPE-1

Background: Cytokines and cytokine antagonists modulate human immunode ficiency virus (HIV) replication in vitro and may be involved in HIV d isease pathogenesis. An understanding of these cytokine networks may s uggest novel treatment strategies for HIV-seropositive persons. Materi als and Methods: U1 cells, a chronically infected promonocytic cell li ne, were stimulated with interleukin 1 alpha (IL-1 alpha), IL-1 beta o r tumor necrosis factor (TNF) for 24 hr. The effects of these cytokine s, and of anti-IL-1 receptor type 1 and type 2 (IL-1RI and II) antibod y, IL-1 receptor antagonist (IL-1Ra), and recombinant human TNF bindin g protein type 1 (rhTBP-1, a form of TNF receptor p55), on HIV-1 repli cation, as measured by ELISA for HIV-1 p24 antigen, were determined. T he effects of IL-1 and IL-1Ra on nuclear factor-kappa B (NF-kappa B) D NA binding activity, as measured by electrophoretic mobility shift ass ays, were also determined. Results: IL-1 alpha and IL-1 beta increased p24 antigen production in a concentration-dependent manner. IL-1Ra co mpletely, and rhTBP-1 partially, suppressed IL-1-induced p24 antigen p roduction. IL-1 increased NF-kappa B DNA binding activity and IL-1Ra b locked this effect. Since IL-1Ra blocks IL-1 from binding to both the IL-1RI and IL-1RII, monoclonal antibodies directed against each recept or were used to ascertain which IL-1R mediates IL-1-induced HIV-1 expr ession. Antibody to the IL-1RI reduced IL-1-induced p24 antigen produc tion. Although anti-IL-1RII antibody blocked the binding of (125)IL-1 alpha, to U1 cells by 99%, this antibody did not affect IL-1-induced p 24 antigen production. IL-1 beta enhanced TNF alpha-induced HIV expres sion when added before or simultaneously with TNF alpha. Conclusions: IL-1 induces HIV-1 expression (via the IL-1RI) and NF-kappa B activity in U1 cells. These effects are blocked by IL-1Ra and partially mediat ed by TNF. IL-1 enhances TNF alpha-induced HN replication in U1 cells.