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Journal of Virology, February 2004, p. 1202-1211, Vol. 78, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.3.1202-1211.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Human Cytomegalovirus Elicits a Coordinated Cellular Antiviral Response via Envelope Glycoprotein B

Karl W. Boehme, Jasbir Singh, Stuart T. Perry, and Teresa Compton*

McArdle Laboratory for Cancer Research, University of Wisconsin—Madison Medical School, University of Wisconsin—Madison, Madison, Wisconsin 53706

Received 1 July 2003/ Accepted 6 October 2003

Previous studies have shown that human cytomegalovirus (CMV) is a potent elicitor of interferon-stimulated gene (ISG) expression. Induction of the interferon pathway does not require replication-competent virus, and envelope glycoprotein B (gB) from CMV is a viral structural component that can directly induce transcription of ISGs. Here we extend these earlier findings by defining the consequences of inducing the interferon pathway. We found that cells respond to CMV or soluble gB by establishing a functional antiviral state within cell types critical in CMV biology, such as fibroblasts and endothelial cells. We have also discovered new insights into the mechanism by which the pathway is initiated. Interferon regulatory factor 3 (IRF3), a key transcriptional regulator of cellular interferon responses, is activated by CMV virions and soluble gB. Thus, IRF3 becomes activated via "outside-in" signal transduction events. This is a novel mechanism of activation of this key transcription factor by viruses. In comparison to soluble gB (gB1-750), which comprises the entire ectodomain of gB, a truncation mutant encompassing only the amino-terminal region of gB (gB1-460) was markedly less effective at inducing antiviral responses. This indicates that the region of gB from residues 461 to 750 is important for initiation of the antiviral response. In addition, CMV and gB establish an antiviral state in alpha/beta interferon null cells, illustrating that primary induction of ISGs by CMV and gB is sufficient to establish the antiviral response and that interferon secretion is not necessary for the antiviral effect. Taken together, our findings reveal that CMV initiates a coordinated antiviral response through contact between gB and an as-yet-unidentified cell surface receptor(s).

* Corresponding author. Mailing address: McArdle Laboratory for Cancer Research, University of Wisconsin—Madison Medical School, University of Wisconsin—Madison, Madison, WI 53706. Phone: (608) 262-1474. Fax: (608) 262-2824. E-mail: tcompton{at}wisc.edu.

Journal of Virology, February 2004, p. 1202-1211, Vol. 78, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.3.1202-1211.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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