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Herpes simplex virus 1-encoded tegument protein VP16 abrogates the production of beta interferon (IFN) by inhibiting NF-κB activation and blocking IFN regulatory factor 3 to recruit its coactivator CBP.

Abstract
Host cells activate innate immune signaling pathways to defend against invading pathogens. To survive within an infected host, viruses have evolved intricate strategies to counteract host immune responses. Herpesviruses, including herpes simplex virus type 1 (HSV-1), have large genomes and therefore have the capacity to encode numerous proteins that modulate host innate immune responses. Here we define the contribution of HSV-1 tegument protein VP16 in the inhibition of beta interferon (IFN-β) production. VP16 was demonstrated to significantly inhibit Sendai virus (SeV)-induced IFN-β production, and its transcriptional activation domain was not responsible for this inhibition activity. Additionally, VP16 blocked the activation of the NF-κB promoter induced by SeV or tumor necrosis factor alpha treatment and expression of NF-κB-dependent genes through interaction with p65. Coexpression analysis revealed that VP16 selectively blocked IFN regulatory factor 3 (IRF-3)-mediated but not IRF-7-mediated transactivation. VP16 was able to bind to IRF-3 but not IRF-7 in vivo, based on coimmunoprecipitation analysis, but it did not affect IRF-3 dimerization, nuclear translocation, or DNA binding activity. Rather, VP16 interacted with the CREB binding protein (CBP) coactivator and efficiently inhibited the formation of the transcriptional complexes IRF-3-CBP in the context of HSV-1 infection. These results illustrate that VP16 is able to block the production of IFN-β by inhibiting NF-κB activation and interfering with IRF-3 to recruit its coactivator CBP, which may be important to the early events leading to HSV-1 infection.
AuthorsJunji Xing, Liwen Ni, Shuai Wang, Kezhen Wang, Rongtuan Lin, Chunfu Zheng
JournalJournal of virology (J Virol) Vol. 87 Issue 17 Pg. 9788-801 (Sep 2013) ISSN: 1098-5514 [Electronic] United States
PMID23824799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Herpes Simplex Virus Protein Vmw65
  • IRF3 protein, human
  • IRF7 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • RELA protein, human
  • Transcription Factor RelA
  • Interferon-beta
  • CREB-Binding Protein
  • CREBBP protein, human
Topics
  • Animals
  • CREB-Binding Protein (metabolism)
  • Chlorocebus aethiops
  • HEK293 Cells
  • HeLa Cells
  • Herpes Simplex Virus Protein Vmw65 (chemistry, genetics, immunology)
  • Herpesvirus 1, Human (genetics, immunology, physiology)
  • Host-Pathogen Interactions (genetics, immunology)
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 (antagonists & inhibitors, metabolism)
  • Interferon Regulatory Factor-7 (metabolism)
  • Interferon-beta (biosynthesis, genetics)
  • Promoter Regions, Genetic
  • Protein Structure, Tertiary
  • Sendai virus (immunology, pathogenicity)
  • Transcription Factor RelA (antagonists & inhibitors, genetics, metabolism)
  • Transcriptional Activation
  • Vero Cells

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