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PMID: 17376932 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Inhibition of transcription of the beta interferon gene by the human herpesvirus 6 immediate-early 1 protein.

Journal of virology ·Vol. 81 ·No. 11 ·2007-06-00 ·Pages 5737-48

Jaworska J, Gravel A, Fink K, Grandvaux N, Flamand L

Abstract

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-beta gene expression. IE1 proteins from both HHV-6 variants were capable of suppressing IFN-beta gene induction. IE1 prevents IFN-beta gene expression triggered by Sendai virus infection, double-stranded RNA (dsRNA) and dsDNA transfection, or the ectopic expression of IFN-beta gene activators such as retinoic inducible gene I protein, mitochondrial antiviral signaling protein, TBK-1, IkappaB kinase epsilon (IKKepsilon), and IFN regulatory factor 3 (IRF3). While the stability of IFN-beta 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 IKKepsilon. Using nuclear extracts and gel shift experiments, we could demonstrate that in the presence of IE1, IRF3 does not bind efficiently to the IFN-beta 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-beta gene induction and likely contributes to favor the establishment of and successful infection of cells with this virus.

MeSH Terms
Cells, Cultured Down-Regulation/physiology Gene Expression Regulation, Viral/physiology Herpesvirus 6, Human/chemistry,physiology Humans Immediate-Early Proteins/physiology Interferon-beta/antagonists & inhibitors,biosynthesis,genetics Jurkat Cells Phosphoproteins/physiology Transcription, Genetic/physiology Transcriptional Activation
Chemicals
Immediate-Early Proteins Phosphoproteins immediate-early 1 protein, human herpesvirus 6 Interferon-beta
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Jaworska Joanna
Rheumatology and Immunology Research Center, Room T1-49, 2705 Laurier Blvd., Quebec, Quebec, Canada G1V 4G2.
Gravel Annie
Fink Karin
Grandvaux Nathalie
Flamand Louis
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.02443-06
Published
2007-06-00
Epub
2007-00-21
Pages
5737-48
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC1900312
Subset
IM
External Links
PubMed source DOI: 10.1128/JVI.02443-06 PMC Full Text View journal details
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