Inhibition of transcription of the beta interferon gene by the human herpesvirus 6 immediate-early 1 protein.
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.
Jaworska
Joanna
J
Rheumatology and Immunology Research Center, Room T1-49, 2705 Laurier Blvd., Quebec, Quebec, Canada G1V 4G2.
Gravel
Annie
A
Fink
Karin
K
Grandvaux
Nathalie
N
Flamand
Louis
L
D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology*; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D015654:Herpesvirus 6, Human / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology*; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D019169:Jurkat Cells; D010750:Phosphoproteins / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation
D017874:Immediate-Early Proteins; D010750:Phosphoproteins; C458509:immediate-early 1 protein, human herpesvirus 6; D016899:Interferon-beta