Herpes simplex virus type 1 infection activates the Epstein-Barr virus replicative cycle via a CREB-dependent mechanism

Cell Microbiol. 2012 Apr;14(4):546-59. doi: 10.1111/j.1462-5822.2011.01740.x. Epub 2012 Jan 18.


The reactivation of latent Epstein-Barr virus (EBV) to lytic replication is important in pathogenesis and requires virus-host cellular interactions. However, the mechanism underlying the reactivation of EBV is not yet fully understood. In the present study, herpes simplex virus type 1 (HSV-1) was shown to induce the reactivation of latent EBV by triggering BZLF1 expression. The BZLF1 promoter (Zp) was not activated by HSV-1 essential glycoprotein-induced membrane fusion. Nevertheless, Zp was activated within 6 h post HSV-1 infection in virus entry-dependent and replication-independent manners. Using a panel of Zp deletion mutants, HSV-1 was shown to promote Zp through a cyclic adenosine monophosphate (cAMP) response element (CRE) located in ZII. The phosphorylated cAMP response element-binding (phos-CREB) protein, the cellular transactivator that binds to CRE, also increased after HSV-1 infection. By transient transfection, cAMP-dependent protein kinase A and HSV-1 US3 protein were found to be capable of activating Zp in CREB- and CRE-dependent manners. The relationship between EBV activation and HSV-1 infection revealed a possible common mechanism that stimulated latent EBV into lytic cycles in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA Viruses / genetics
  • DNA Viruses / metabolism
  • Gene Expression Regulation, Viral
  • HEK293 Cells
  • Herpesvirus 1, Human / genetics
  • Herpesvirus 1, Human / metabolism
  • Herpesvirus 1, Human / pathogenicity*
  • Herpesvirus 1, Human / physiology
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / metabolism
  • Herpesvirus 4, Human / pathogenicity*
  • Herpesvirus 4, Human / physiology
  • Host-Pathogen Interactions
  • Humans
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Sequence Deletion
  • Time Factors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transfection
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virus Activation*
  • Virus Internalization
  • Virus Latency*


  • BZLF1 protein, Herpesvirus 4, Human
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Trans-Activators
  • Viral Proteins
  • Protein Serine-Threonine Kinases
  • US3 protein, Human herpesvirus 1