Human cytomegalovirus (HCMV) 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-β) 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-β expression. We demonstrate that the induction of IFN-β during HCMV infection requires the activation of both the IRF-3 and the NFκB pathways. Therefore, IE86 may target either pathway to block IFN-β 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 NFκB to the IFN-β promoter, resulting in attenuation of IFN-β and NFκB-dependent gene expression. Furthermore, IE86 expression inhibits tumor necrosis factor alpha-induced NFκB DNA binding and target gene expression. Together, these results identify IE86 as a NFκB antagonist, which results in the suppression of NFκB-dependent cytokine and chemokine gene expression.
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