The cytokine-stimulated activation of NF-kappaB has been shown to be essential for the expression of genes controlled by the HIV LTR and for the expression of the AIDS virus itself. Our recent studies demonstrate that depleting intracellular glutathione (GSH) markedly facilities NF- kappaB activation. We have shown that N-acetylcysteine (NAC), a non- toxic drug used clinically to replenish GSH and to scavenge intracellular oxidants in paracetamol (Tylenol) poisoning, replenishes GSH and blocks cytokine-stimulated HIV replication in acutely and chronically infected cell lines and in normal peripheral blood mononuclear cells infected in vitro. These findings are explained by the recognition of a thiol-sensitive step in the signal transduction pathway through which cytokines such as TNF-alpha stimulated NF-kappaB activation. Since intracellular GSH levels tend to be low in HIV-infected individuals and TNF-alpha levels tend to be high, our findings suggest that the replenishment of intracellular thiols (e.g., by continued treatment with NAC) could be beneficial clinically. For patients with frank AIDS, NAC therapy could provide an effective means for overcoming the toxicity due to excessive cytokine stimulation (e.g., wasting) and possibly for slowing the progression of the HIV infection. For ARC patients, it could interrupt the cytokine/viral expression cycle that results in physical deterioration and progression to AIDS. Finally, for asymptomatic, HIV-positive individuals, it could help to maintain the virus in a latent state and thus prevent initiation of the progression to AIDS. Studies proposed here concentrate on further exploration of the mechanisms through which intracellular thiols influence signal transduction, transcription factor production/activation and the cytokine-stimulated expression of genes in general and HIV in particular.
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