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  • Original Paper
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HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators

Oncogene volume 20, pages 800–811 (2001)Cite this article

Abstract

Human herpes virus 8 (HHV-8) has developed unique mechanisms for altering cellular proliferative and apoptotic control pathways by incorporating viral homologs to several cellular regulatory genes into its genome. One of the important pirated genes encoded by the ORF K9 reading frame is a viral homolog of the interferon regulatory factors (IRF), a family of cellular transcription proteins that regulates expression of genes involved in pathogen response, immune modulation and cell proliferation. vIRF-1 has been shown to downregulate the interferon- and IRF-mediated transcriptional activation of ISG and murine IFNA4 gene promoters. In this study we demonstrate that vIRF-1 efficiently inhibited virus-induced expression of endogenous interferon B, CC chemokine RANTES and CXC chemokine IP-10 genes. Co-expression analysis revealed that vIRF-1 selectively blocked IRF-3 but not IRF-7-mediated transactivation. vIRF-1 was able to bind to both IRF-3 and IRF-7 in vivo as detected by coimmunoprecipitation analysis, but did not affect IRF-3 dimerization, nuclear translocation and DNA binding activity. Rather, vIRF-1 interacted with the CBP/p300 coactivators and efficiently inhibited the formation of transcriptionally competent IRF-3-CBP/p300 complexes. These results illustrate that vIRF-1 is able to block the early stages of the IFN response to virus infection by interfering with the activation of IRF-3 responsive, immediate early IFN genes.

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Acknowledgements

The authors wish to thank Drs Jae Jung, Margaret Offermann, Paula Pitha, Xiangjiao Yang and Illka Julkunen for reagents used in this study and members of the Molecular Oncology Group, Lady Davis Institute for helpful discussions. This research was supported by grants from Canadian Institutes of Health Research and Cancer Research Society Inc. CANVAC, Network Centers of Excellence, and the Italian Aids Project. R Lin was supported in part by a Fraser Monat McPherson Fellowship from McGill University, P Genin by a FRSQ post-doctoral Fellowship, Y Mamane by a MRC Studentship and J Hiscott by a MRC Senior Scientist award.

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Authors and Affiliations

  1. Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, H3T IE2, Canada

    Rongtuan Lin, Pierre Genin, Yael Mamane, Marco Sgarbanti & John Hiscott

  2. Department of Microbiology and Immunology, McGill University, Montreal, H3T IE2, Canada

    Yael Mamane & John Hiscott

  3. Department of Medicine, McGill University, Montreal, H3T 1E2, Canada

    Rongtuan Lin, Pierre Genin & John Hiscott

  4. Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL 33136, Florida

    William J Harrington Jr, Glen N Barber & John Hiscott

  5. Istituto Superiore Di Sanita, Rome, 00161, Italy

    Marco Sgarbanti & Angela Battistini

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Lin, R., Genin, P., Mamane, Y. et al. HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators. Oncogene 20, 800–811 (2001). https://doi.org/10.1038/sj.onc.1204163

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