NF-κB protects HIV-1-infected myeloid cells from apoptosis

HIV-1 infection of primary monocytic cells and myeloid cell lines results in sustained NF-kappa B activation. Recently, NF-kappa B induction has been shown to play a role in protecting cells from programmed cell death. In the present study, we sought to investigate whether constitutive NF-kappa B activity in chronically HIV-1-infected promonocytic U937 (U9-IIIB) and myeloblastic PLB-985 (PLB-IIIB) cells affects apoptotic signaling. TNF alpha and cycloheximide caused infected cells to undergo apoptosis more rapidly than parental U937 and PLB-985 cells. Inhibition of TNF alpha-induced NF-kappa B activation using the antioxidant N-acetylcysteine (NAC) resulted in increased apoptosis in both U937 and U9-IIIB cells, while preactivation of NF-kappa B with the non-apoptotic inducer IL-1 beta caused a relative decrease in apoptosis. Inhibition of constitutive NF-kappa B activity in U9-IIIB and PLB-IIIB cells also induced apoptosis, suggesting that NF-kappa B protects cells from a persistent apoptotic signal. TNF alpha plus NAC treatment resulted in a marked decrease in Bcl-2 protein levels in HIV-1-infected cells, coupled with an increase in Bar protein compared to uninfected cells, suggesting that the difference in susceptibility to TNF alpha-induced apoptosis may relate to the differences in relative levels of Bcl-2 and Bar. The protective role of NF-kappa B in blocking TNF alpha- and HIV-l-induced apoptosis was supported by studies in Jurkat T cells engineered to express I kappa B alpha repressor mutants (TD-I kappa B) under the control of a tetracycline-responsive promoter. Cells underwent apoptosis in response to TNF alpha only when NF-kappa B activation was inhibited by TD-I kappa B expression. As was observed for the U9-IIIB cells, TNF alpha treatment also induced a marked decrease in Bcl-2 protein levels in TD-I kappa B expressing cells. These experiments demonstrate that apoptotic signaling is perturbed in HIV-1-infected U9-IIIB cells and indicate that NF-kappa B activation may play an additional protective role against HIV-l-induced apoptosis in myeloid cells, (C) 1998 Academic Press.