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 reported that a soluble, dimeric form of the 80 kD TNF receptor (FcTNFR) could effectively block TNF-mediated induction of 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 FcTNFR. The cytokine, interleukin-4 (IL-4) has been reported to both enhance and inhibit replication of HIV-1 in human monocytes in vitro, depending on the state of cellular differentiation. We have recently tested a purified form of soluble human IL-4 receptor (sIL-4R) for their ability to modulate the effects of IL-4 on HIV-infected, monocyte-derived macrophages. We find that IL-4, when present throughout infection, inhibits HIV-1 replication in human macrophages. In contrast, IL-4 added at later times during the course of infection enhanced HIV replication. We also found that sIL4R, when used at low ratios with respect to the IL-4 concentration, increased the IL-4 mediated inhibition of virus replication in differentiated macrophages. However, when sIL-4R were present in 100-fold excess of IL-4, the inhibitory effects of the cytokine were reversed. These results suggest that sIL-4R can augment the biological effects of IL-4 when used at concentrations equivalent to IL-4, but at a high molar excess they function as an antagonist. Similar results were observed in preliminary experiments using an antibody specific for IL-4. These results provide some insight into the complex nature of cytokine/cytokine receptor networks that may exist in vivo, and the potential complications that may result from therapeutic use of soluble cytokine receptors.