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Journal of Virology, June 2007, p. 5737-5748, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02443-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhibition of Transcription of the Beta Interferon Gene by the Human Herpesvirus 6 Immediate-Early 1 Protein{triangledown}

Joanna Jaworska,1 Annie Gravel,1 Karin Fink,2 Nathalie Grandvaux,2 and Louis Flamand1*

Laboratory of Virology, Rheumatology and Immunology Research Center, CHUQ Research Center, and Faculty of Medicine, Laval University, Quebec, Quebec, Canada,1 Department of Biochemistry, Faculty of Medicine, University of Montreal, and CHUM Research Center-Hôpital St.-Luc, Montreal, Quebec, Canada2

Received 6 November 2006/ Accepted 9 March 2007

Human herpesviruses (HHV) are stealth pathogens possessing several decoy or immune system evasion mechanisms favoring their persistence within the infected host. Of these viruses, HHV-6 is among the most successful human parasites, establishing lifelong infections in nearly 100% of individuals around the world. To better understand this host-pathogen relationship, we determined whether HHV-6 could interfere with the development of the innate antiviral response by affecting interferon (IFN) biosynthesis. Using inducible cell lines and transient transfection assays, we have identified the immediate-early 1 (IE1) protein as a potent inhibitor of IFN-ß gene expression. IE1 proteins from both HHV-6 variants were capable of suppressing IFN-ß gene induction. IE1 prevents IFN-ß gene expression triggered by Sendai virus infection, double-stranded RNA (dsRNA) and dsDNA transfection, or the ectopic expression of IFN-ß gene activators such as retinoic inducible gene I protein, mitochondrial antiviral signaling protein, TBK-1, I{kappa}B kinase {varepsilon} (IKK{varepsilon}), and IFN regulatory factor 3 (IRF3). While the stability of IFN-ß mRNA is not affected, IE1-expressing cells have reduced levels of dimerized IRF3 and nucleus-translocated IRF3 in response to activation by TBK-1 or IKK{varepsilon}. Using nuclear extracts and gel shift experiments, we could demonstrate that in the presence of IE1, IRF3 does not bind efficiently to the IFN-ß promoter sequence. Overall, these results indicate that the IE1 protein of HHV-6, one of the first viral proteins synthesized upon viral entry, is a potent suppressor of IFN-ß gene induction and likely contributes to favor the establishment of and successful infection of cells with this virus.

* Corresponding author. Mailing address: Rheumatology and Immunology Research Center, Room T1-49, 2705 Laurier Blvd., Quebec, Quebec, Canada G1V 4G2. Phone: (418) 656-4141, ext. 46164. Fax: (418) 654-2765. E-mail: Louis.Flamand{at}crchul.ulaval.ca

{triangledown} Published ahead of print on 21 March 2007.

Journal of Virology, June 2007, p. 5737-5748, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02443-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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  • Randall, R. E., Goodbourn, S. (2008). Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol. 89: 1-47 [Abstract] [Full Text]  


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