HIV TYPE-1 GLYCOPROTEIN-120 AMPLIFIES TUMOR NECROSIS FACTOR-INDUCED NF-KAPPA-B ACTIVATION IN JURKAT CELLS

This article demonstrates that human immunodeficiency virus type 1 (HI V-1) gp120 amplifies the activity of tumor necrosis factor alpha (TNF- alpha), a cytokine that stimulates HIV-1 replication through activatio n of NF-kappa B. In CD4-positive Jurkat cells, gp120 potentiates TNF-i nduced NF-kappa B activation. TNF-mediated activation of NF-kappa B is known to involve the intracellular formation of reactive oxygen inter mediates (ROIs). Accordingly, we examined the influence of gp120 on th e cellular redox state. We found that gp120-modulated TNF-induced NK-k appa B activation was inhibited by the antioxidant butylated hydroxyan isole, indicating the involvement of redox-dependent mechanisms. In ad dition, we showed that gp120 induces intracellular formation of hydrog en peroxide, which is accompanied by a decrease in the ratio of glutat hione to glutathione disulfide. In contrast, in the p56(lck)-deficient J.CaM1.6 T cell line, a derivative of the Jurkat cell line, gp120 was unable to stimulate hydrogen peroxide, to decrease the ratio of GSH t o GSSG, and has no effect on TNF-induced NF-kappa B activation. This d emonstrated that p56(lck) protein tyrosine kinase plays an active role in transmitting a signal that increases the oxidative state of the ce ll and as a consequence amplifies TNF-mediated NF-kappa B DNA binding. We have demonstrated that Tat protein decreased both the Mn-dependent superoxide dismutase (MnSOD) and the cellular glutathione content (GS H). Here we show that, in contrast to Tat, gp120 is unable to inhibit activity and expression of MnSOD and to decrease GSH content. Taken to gether, our data suggest that gp120 potentiates TNF-induced NF-kappa B activation by stimulating a signal pathway that involves p56(lck) and the increased formation of reactive oxygen intermediates such as H2O2 . These findings may be relevant for the regulation of HIV-1 replicati on in T cells.