Human cytomegalovirus IE86 attenuates virus- and tumor necrosis factor alpha-induced NFKB-dependent gene expression

Human cytomegalovirus (HCW) infection regulates a number of genes involved in the host antiviral response. We have previously reported that HCMV attenuates the expression of beta interferon (IFN-beta) and a number of proinflammatory chemokines, and this attenuation is mediated by the HCMV immediate-early protein IE86. The present study seeks to identify the mechanism by which IE86 blocks IFN-beta expression. We demonstrate that the induction of IFN-beta during HCMV infection requires the activation of both the IRF-3 and the NF kappa B pathways. Therefore, IE86 may target either pathway to block IFN-beta expression. Our results show that IE86 does not block IRF-3 phosphorylation, dimerization, nuclear translocation, or target gene expression. However, using gel shift analysis, we demonstrate that IE86 efficiently inhibits virus-induced binding of NF kappa B to the IFN-beta promoter, resulting in attenuation of IFN-beta and NF kappa B-dependent gene expression. Furthermore, IE86 expression inhibits tumor necrosis factor alpha-induced NF kappa B DNA binding and target gene expression. Together, these results identify IE86 as a NF kappa B antagonist, which results in the suppression of NF kappa B-dependent cytokine and chemokine gene expression.