Our previous studies have shown that the cytokine, tumor necrosis factor-a (TNF), stimulates HIV-1 replication in chronically infected T lymphocytic and monocytic cell lines and that a soluble, dimeric form of the 80 kD TNF receptor (TNFR:Fc) could effectively block this induction. The ratio of receptor to TNF was critical, with optimal inhibition requiring a 5-fold molar excess of TNFR:Fc. The cytokine, interleukin-4 (IL-4), has been reported to both enhance and inhibit replication of HIV-1 in human monocytes/macrophages (MO) in vitro, depending on the state of cellular differentiation. We tested purified soluble human IL-4 receptors (sIL-4R) for their ability to modulate the effects of IL-4 on HIV-infected MO. We find that IL-4, when present throughout infection, inhibits HIV-1 replication in differentiated macrophages. In contrast, IL-4 added at later times during infection enhanced HIV replication. In addition, 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 100-fold in excess of IL-4, the inhibitory effects of the cytokine were reversed. These results suggest that sIL-4R can function as an agonist to 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. The comparative effects of human and murine soluble IL-4 receptors, as well as anti-IL-4 antibodies are currently under investigation. These results will provide more 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. TNF has been shown to stimulate HIV-1 replication in vitro via activation of the cellular transcription factor, NF-kB. Oxidative stress also induces HIV replication through activation of NF-kB, and this effect could be reduced by selenium supplementation. The trace element, selenium, is incorporated into proteins as the amino acid selenocysteine, is essential for a functional immune system, can inhibit the expression of some viruses, and has been suggested as a therapeutic supplement in HIV infection. Since TNF and oxidative stress induce HIV by the same mechanism, we evaluated the effect of Se on TNF-induced HIV. We find that TNF-mediated induction of HIV-1 expression in both chronically infected T lymphocytic and monocytic cells can be reduced by selenium supplementation. Although selenium failed to suppress acute HIV infection of primary human T lymphocytes and monocytes, it did reduce the enhancing effects of TNF on acute HIV infection of monocytes, but not T cells. Thus, selenium supplementation may have some benefit as a supportive therapy in HIV-infected patients but, alone, would be incapable of ablating the detrimental effects of TNF.
