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Journal of Virology, May 2005, p. 6419-6431, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6419-6431.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Rhesus Cytomegalovirus Particles Prevent Activation of Interferon Regulatory Factor 3{dagger}

Victor DeFilippis and Klaus Früh*

Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon 97006

Received 28 June 2004/ Accepted 29 December 2004

One of the most important innate host defense mechanisms against viral infection is the induction of interferon (IFN)-stimulated genes (ISGs). Immediately upon entry, viruses activate interferon-regulatory factor 3 (IRF3), as well as nuclear factor {kappa}B (NF-{kappa}B), which transactivate a subset of ISGs, proinflammatory genes, as well as IFN genes. Most large DNA viruses exhibit countermeasures against induction of this response. However, whereas human cytomegalovirus (HCMV) inhibits IFN-dependent induction of ISGs, IFN-independent induction of ISGs is observed both in the presence and, even moreso, in the absence of viral gene expression. Rhesus CMV (RhCMV) is an emerging animal model for HCMV sharing important similarities in primary structure, epidemiology, and pathogenesis. To determine whether RhCMV would similarly induce ISGs, we performed DNA microarray and quantitative PCR analysis of ISG expression in rhesus fibroblasts infected with RhCMV or HCMV. In contrast to HCMV, however, RhCMV did not induce expression of ISGs or proinflammatory genes at any time after infection. Moreover, dimerization and nuclear accumulation of IRF3, readily observed in HCMV-infected cells, was absent from RhCMV-infected cells, whereas neither virus seemed to activate NF{kappa}B. RhCMV also blocked IRF3 activation by live or UV-inactivated HCMV, suggesting that RhCMV inhibits viral IRF3 activation and the resultant ISG induction with extraordinary efficiency. Since infection during inhibition of protein expression by cycloheximide or inactivation of viral gene expression by UV treatment did not trigger IRF3 activation or ISG expression by RhCMV, we conclude that RhCMV virions contain a novel inhibitor of IFN-independent viral induction of ISG expression by IRF3.

* Corresponding author. Mailing address: Vaccine and Gene Therapy Institute, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006. Phone: (503) 418-2735. Fax: (503) 418-2701. E-mail: fruehk{at}ohsu.edu.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, May 2005, p. 6419-6431, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6419-6431.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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