Cytomegalovirus Activates Interferon Immediate-Early Response Gene Expression and an Interferon Regulatory Factor 3-Containing Interferon-Stimulated Response Element-Binding Complex

ABSTRACT

Interferon establishes an antiviral state in numerous cell types through the induction of a set of immediate-early response genes. Activation of these genes is mediated by phosphorylation of latent transcription factors of the STAT family. We found that infection of primary foreskin fibroblasts with human cytomegalovirus (HCMV) causes selective transcriptional activation of the alpha/beta-interferon-responsive ISG54 gene. However, no activation or nuclear translocation of STAT proteins was detected. Activation of ISG54 occurs independent of protein synthesis but is prevented by protein tyrosine kinase inhibitors. Further analysis revealed that HCMV infection induced the DNA binding of a novel complex, tentatively called cytomegalovirus-induced interferon-stimulated response element binding factor (CIF). CIF is composed, at least in part, of the recently identified interferon regulatory factor 3 (IRF3), but it does not contain the STAT1 and STAT2 proteins that participate in the formation of interferon-stimulated gene factor 3. IRF3, which has previously been shown to possess no intrinsic transcriptional activation potential, interacts with the transcriptional coactivator CREB binding protein, but not with p300, to form CIF. Activating interferon-stimulated genes without the need for prior synthesis of interferons might provide the host cell with a potential shortcut in the activation of its antiviral defense.

ACKNOWLEDGMENTS

We thank Andrew Larner and Keiko Ozata for their generous gifts of STAT1 and STAT2 and of the IRF1 and IRF2 antisera, respectively. We are also grateful to Robert Rickert for a critical reading of the manuscript. Antisera to CBP and p300 were generously provided by Pier Lorenzo Puri.

K.M. is a recipient of a fellowship from the Markey Foundation. This work was supported by NIH grants CA34729 (D.S.) and CA50773 (N.R.) and NIH training grant AI07384 (S.R.).