Identification of an important immunological difference between virulent varicella-zoster virus and its avirulent vaccine: viral disruption of dendritic cell instruction

J Immunol. 2010 Jul 1;185(1):488-97. doi: 10.4049/jimmunol.0902817. Epub 2010 Jun 4.


Virulent varicella-zoster virus (VZV) can spread in immunocompetent humans, resulting in symptoms mostly of the skin. In contrast, vaccine Oka (V-Oka), the attenuated VZV vaccine strain, only rarely causes clinical reactions. The mechanisms underlying these pathogenetic differences are unclear. In this study, we comparatively analyzed the ability of virulent VZV and V-Oka to modulate instruction of dendritic cells (DCs) by innate signals. DCs isolated from normal human skin were susceptible to infection with VZV and V-Oka. Moreover, inflammatory DCs, which play a crucial role in the stimulation of Th1 immune responses, accumulated in herpes zoster lesions. Infection of inflammatory DCs generated in vitro with virulent VZV or V-Oka resulted in upregulation of CD1c. Upon coculture with CD1c-restricted innate cells, DCs developed a mature phenotype whether infected with virulent VZV or V-Oka. Intriguingly, a striking difference was detected on the functional level. The release of IFN-gamma and IL-12, the signature cytokines of Th1 responses, was enhanced by V-Oka but blocked by virulent VZV. V-Oka and virulent VZV efficiently synergized with CD40L, eliminating the possibility that CD40 signaling was a target of VZV-associated immune evasion. Instead, virulent VZV selectively interfered with signaling through TLR2, which is known to sense VZV. Thus, virulent VZV subverts Th1-promoting instruction of human DCs by blocking TLR2-mediated innate signals that prime IL-12 production by DCs. Taken together, our results demonstrate a novel immune-evasion mechanism of virulent VZV that has been lost during the attenuation process leading to the VZV vaccine strain.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Chickenpox Vaccine / immunology*
  • Coculture Techniques
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / virology*
  • Herpes Zoster / immunology
  • Herpes Zoster / virology
  • Herpesvirus 3, Human / immunology*
  • Herpesvirus 3, Human / isolation & purification
  • Herpesvirus 3, Human / pathogenicity*
  • Herpesvirus Vaccines / immunology*
  • Humans
  • Immune Evasion / immunology
  • Interleukin-12 / biosynthesis
  • Middle Aged
  • Monocytes / cytology
  • Monocytes / immunology
  • Monocytes / virology
  • Signal Transduction / immunology*
  • Th1 Cells / immunology
  • Th1 Cells / virology
  • Vaccines, Attenuated / immunology
  • Virulence


  • Chickenpox Vaccine
  • Herpesvirus Vaccines
  • Vaccines, Attenuated
  • Interleukin-12