ABSTRACT
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.
The immediate early genes of human cytomegalovirus upregulate tumor necrosis factor-alpha gene expression.