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Journal of Virology, October 2004, p. 10995-11006, Vol. 78, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.20.10995-11006.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Major Human Cytomegalovirus Structural Protein pp65 (ppUL83) Prevents Interferon Response Factor 3 Activation in the Interferon Response

Davide A. Abate, Shinya Watanabe,{dagger} and Edward S. Mocarski*

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California

Received 10 May 2004/ Accepted 24 May 2004

We have identified a cytomegalovirus virion protein capable of modulating the rapid induction of an interferon-like response in cells that follows virus binding and penetration. Functional genomics revealed a role for the major cytomegalovirus structural protein, pp65 (ppUL83), in counteracting this response. The underlying mechanism involves a differential impact of this structural protein on the regulation of interferon response factor 3 (IRF-3). In contrast, NF-{kappa}B is activated independent of pp65, and neither STAT1 nor STAT3 becomes activated by either virus. pp65 is sufficient to prevent the activation of IRF-3 when introduced alone into cells. pp65 acts by inhibiting nuclear accumulation of IRF-3 and is associated with a reduced IRF-3 phosphorylation state. Thus, this investigation shows that the major structural protein of cytomegalovirus is committed to the modulation of the IRF-3 response, a primary mediator of the type I interferon response. By subverting IRF-3, the virus escapes throwing a central alarm devoted to both immediate antiviral control and regulation of the immune response.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, D 347 Fairchild Science Bldg., Stanford University School of Medicine, Stanford, CA 94305-5124. Phone: (650) 723-6435. Fax: (650) 723-1606. E-mail: mocarski{at}stanford.edu.

{dagger} Present address: Department of Clinical Informatics, Tokyo Medical Dental University School of Medicine, Bunkyo-ku, Tokyo 113, Japan.

Journal of Virology, October 2004, p. 10995-11006, Vol. 78, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.20.10995-11006.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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