NF‐κB activation upon interaction of HIV‐1 envelope glycoproteins with cell surface CD4 involves IκB kinases

Abstract

Human immunodeficiency virus type-1 envelope glycoprotein (gp120 ^env ) binding to cell surface CD4 receptor triggers a broad range of intracellular effects leading to T cell activation and cell cycle entry. Among these effects we and others previously reported on the nuclear translocation of the nuclear factor-κB (NF-κB) transcription factor. The present work further investigates the signal transduction pathways involved in gp120 ^env -induced NF-κB activation. We demonstrate that gp120 ^env –CD4 interaction stimulates the hyperphosphorylation of IκB-α inhibitory protein. Conversely, overexpression of a dominant-negative IκB-α transgene mutated at S32 and S36 residues, abolishes gp120 ^env -induced NF-κB activation. IκB kinases (IKKs) activity was found to be selectively enhanced following CD4 engagement with gp120 ^env and to mediate the phosphorylation of IκB-α while co-transfection experiments using dominant-negative forms of IKKs inhibited gp120 ^env -induced NF-κB activation. Taken together, these results confirm that IKKs complex play a key role in gp120 ^env -induced NF-κB activation.