The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), induce a variety of biochemical and physiological changes in nearly every organ and tissue. IL-1 and TNF also activate NF-kB which is thought to play a role in the control of HIV-1 replication. There are two naturally occurring proteins which block the biological effects of IL-1 and TNF: the IL-1 receptor antagonist (IL-1ra), which competes with IL-1 for occupancy of IL-1 receptors, and the TNF binding protein-1 (TBP-1), which binds TNF and prevents its interaction with the TNF receptor. We hypothesize that the relative amounts of these cytokines and their natural antagonists, IL-1ra and TBP-1, influence the replication of HIV-1 and by extension, the development of HIV-1 related illness. IL-1ra and TBP-1 will be used to block the effects of their agonist cytokines on HIV-1 replication in peripheral blood mononuclear cells (PBMC) and a monoblastoid cell line (A3.5 cells). PBMC from HIV-1 seronegative donors and A3.5 cells infected in-vitro with HIV-1 and PBMC from HIV-1 seropositive donors will be studied. IL-1ra and TBP-1 production in- vitro will be determined in HIV-1-infected PBMC and A3.5 cells in order to study possible dysregulation of cytokine antagonism. The cytokines IL-1alpha, IL-1beta2, IL-6, GM-CSF, and IL-8 will also be measured during HIV-1 infection and during blockade using saturating concentrations of IL-1ra and TBP-1. Antisense IL-1 and IL-1ra mRNA will be used to assess the role of intracellular IL-1 in HIV-1 replication and on the synthesis of other cytokines. The effect of endogenous histamine production will be studied using cimetidine. In addition, an analog of the amino acid taurine (taurolidine) will be added to infected PBMC and A3.5 cells in order to observe an effect on HIV-1 replication of this nonspecific IL-1 and TNF inhibitor. Key experiments will be repeated using peripheral blood monocytes from HIV-1 seronegative donors separated by elutriation and infected in-vitro with a monocyte-tropic strain of HIV-1. These studies offer a unique opportunity to define the role of IL-1 and TNF during HIV-1 infection by using their antagonists. A benefit of these studies is the possibility of direct clinical applications of these cytokine antagonists to the treatment of HIV-1 related disease.
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