Varicellazoster virus activates CREB, and inhibition of the pCREB-p300/CBP interaction inhibits viral replication in vitro and skin pathogenesis in vivo

Sylvie François, Nandini Sen, Bryan Mitton, Xiangshu Xiao, Kathleen M. Sakamoto, Ann Arvin

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Varicella-zoster virus (VZV) is an alphaherpesvirus that causes varicella upon primary infection and zoster upon reactivation from latency in sensory ganglion neurons. The replication of herpesviruses requires manipulation of cell signaling pathways. Notably, CREB, a factor involved in the regulation of several cellular processes, is activated upon infection of T cells with VZV. Here, we report that VZV infection also induced CREB phosphorylation in fibroblasts and that XX-650-23, a newly identified inhibitor of the phosphorylated-CREB (pCREB) interaction with p300/CBP, restricted cell-cell spread of VZV in vitro. CREB phosphorylation did not require the viral open reading frame 47 (ORF47) and ORF66 kinases encoded by VZV. Evaluating the biological relevance of these observations during VZV infection of human skin xenografts in the SCID mouse model of VZV pathogenesis showed both that pCREB was upregulated in infected skin and that treatment with XX-650-23 reduced infectiousvirus production and limited lesion formation compared to treatment with a vehicle control. Thus, processes of CREB activation and p300/CBP binding are important for VZV skin infection and may be targeted for antiviral drug development.

Original languageEnglish (US)
Pages (from-to)8686-8697
Number of pages12
JournalJournal of Virology
Volume90
Issue number19
DOIs
StatePublished - 2016

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Human herpesvirus 3
Human Herpesvirus 3
virus replication
skin (animal)
pathogenesis
Viruses
viruses
Skin
Virus Diseases
infection
phosphorylation
Phosphorylation
antiviral agents
Sensory Ganglia
SCID Mice
Chickenpox
In Vitro Techniques
Herpesviridae
Herpes Zoster
Sensory Receptor Cells

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Varicellazoster virus activates CREB, and inhibition of the pCREB-p300/CBP interaction inhibits viral replication in vitro and skin pathogenesis in vivo. / François, Sylvie; Sen, Nandini; Mitton, Bryan; Xiao, Xiangshu; Sakamoto, Kathleen M.; Arvin, Ann.

In: Journal of Virology, Vol. 90, No. 19, 2016, p. 8686-8697.

Research output: Contribution to journalArticle

François, Sylvie ; Sen, Nandini ; Mitton, Bryan ; Xiao, Xiangshu ; Sakamoto, Kathleen M. ; Arvin, Ann. / Varicellazoster virus activates CREB, and inhibition of the pCREB-p300/CBP interaction inhibits viral replication in vitro and skin pathogenesis in vivo. In: Journal of Virology. 2016 ; Vol. 90, No. 19. pp. 8686-8697.
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