MODULATION OF HIV-1 REPLICATION BY CYTOKINES AND SOLUBLE CYTOKINE RECEPTORS

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We have previously shown that the inflammatory cytokine, tumor necrosis factor- a (TNF- a), can stimulate human immunodeficiency virus type 1(HIV-1) replication in chronically and acutely infected T lymphocytic and monocytic cell lines. This activation is linked to TNF activation of the cellular transcription factor, NF-kB. We subsequently tested the ability of two forms of soluble recombinant type 1 (p80) TNF receptor to inhibit TNF-induced HIV activation in vitro. One form of the receptor was a monomer containing the entire 234 residues of the extracellular (ligand-binding) portion of p80 (M-TNFR); the second form was a homodimer chimeric protein containing these same residues fused to a truncated human IgG1 immunoglobulin chain (Fc-TNFR). The soluble TNF receptor dimer proved to be most effective at blocking the TNF- induced HIV-1 expression in both monocytic and lymphocytic cell lines. The ratio of receptor to TNF was critical, with optimal inhibition requiring a five-fold molar excess of Fc-TNFR. Lower ratios of Fc-TNFR either failed to inhibit or actually enhanced virus expression. All concentrations of M-TNFR tested appeared to enhance TNF-mediated HIV expression. These data were publiished in PNAS (USA), volume 90, pp. 2335-2339 (1993). Interleukin-4 (IL-4) has been reported to either enhance or inhibit replication of HIV-1 in human monocytes in vitro, depending on their state of differentiation. We are currently testing a purified form of soluble human IL-4 receptor (sIL-4R) for its ability to modulate these effects. Our results thus far reveal that sIL4R used at low ratios with respect to the IL-4 concentration increase the IL-4 mediated inhibition of virus replication in differentiated monocytes (macrophages). However, when sIL-4R was present in 100-fold excess of IL-4, the inhibitory effects of the cytokine are reversed. These results suggest that sIL-4R augments the biological effects of IL-4 when used at concentrations equivalent to IL-4, but at a high molar excess functions as an antagonist.