Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine essential for defense against intracellular pathogens is often elevated in the plasma of patients with HIV infection. The increased production of TNF-alpha in late stages of HIV disease has been postulated to be an important factor in disease progression by causing increased HIV relication. Concentrations of soluble TNF Type II receptors are predictors of disease progression and death, suggesting that TNF alpha production is of clinical significance. We postulate that diseases associated with chronic elevations in TNF-alpha production such as rheumatoid arthritis and AIDS may be more responsive to blockade of TNF receptors than acute diseases such as septic shock. Since IL-6 activity is inducible through induction of TNF and since IL-2 administration increases both plasma levels of TNF and IL-6, we propose to test the activity of TNFR:Fc on IL-2 induced, presumably TNF-dependent, IL-6 levels that are increased during infusion of rh IL-2. ACTG 928, a nested substudy of ACTG 328, is designed as a test of concept to determine whether soluble TNF receptor can diminish IL-6 levels and/or TNF bioactivity in subjects with HIV infection who are receiving IL-2. The results of this prospective substudy will provide important information regarding cytokine regulation and toxicities during infusions of IL-2 that may permit the design of simple, more readily tolerated IL-2 regimens for widespread administration and potentially provide preliminary data to support pursuing TNFR:Fc as an adjunctive anti-HIV therapy.
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