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Journal of Virology, December 2007, p. 13092-13104, Vol. 81, No. 23
0022-538X/07/$08.00+0     doi:10.1128/JVI.01378-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Varicella-Zoster Virus Modulates NF-B Recruitment on Selected Cellular Promoters

GIGA-Research, Virology and Immunology Unit, GIGA B34, University of Liège, B-4000 Liège, Belgium

Received 25 June 2007/ Accepted 31 August 2007

Intercellular adhesion molecule 1 (ICAM-1) expression is down-regulated in the center of cutaneous varicella lesions despite the expression of proinflammatory cytokines such as gamma interferon and tumor necrosis factor alpha (TNF-). To study the molecular basis of this down-regulation, the ICAM-1 induction of TNF- was analyzed in varicella-zoster virus (VZV)-infected melanoma cells (MeWo), leading to the following observations: (i) VZV inhibits the stimulation of icam-1 mRNA synthesis; (ii) despite VZV-induced nuclear translocation of p65, p52, and c-Rel, p50 does not translocate in response to TNF-; (iii) the nuclear p65 present in VZV-infected cells is no longer associated with p50 and is unable to bind the proximal NF-B site of the icam-1 promoter, despite an increased acetylation and accessibility of the promoter in response to TNF-; and (iv) VZV induces the nuclear accumulation of the NF-B inhibitor p100. VZV also inhibits icam-1 stimulation of TNF- by strongly reducing NF-B nuclear translocation in MRC5 fibroblasts. Taken together, these data show that VZV interferes with several aspects of the immune response by inhibiting NF-B binding and the expression of target genes. Targeting NF-B activation, which plays a central role in innate and adaptive immune responses, leads to obvious advantages for the virus, particularly in melanocytes, which are a site of viral replication in the skin.

Published ahead of print on 12 September 2007.