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NF-B-Mediated Activation of the Chemokine CCL22 by the Product of the Human Cytomegalovirus Gene UL144 Escapes Regulation by Viral IE86

Department of Medicine, University of Cambridge, Level 5 Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom,¹ Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Campus Universidad Autonoma, 28049 Madrid, Spain,² Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan³

Received 2 October 2007/ Accepted 6 February 2008

The product of the human cytomegalovirus (HCMV) gene UL144, expressed at early times postinfection, is located in the UL/b' region of the viral genome and is related to members of the tumor necrosis factor receptor superfamily, but it does not bind tumor necrosis factor superfamily ligands. However, UL144 does activate NF-B, resulting in NF-B-mediated activation of the cellular chemokine CCL22. Consistent with this finding, isolates of HCMV lacking the UL/b' region show no such activation of CCL22. Recently, it has been suggested that activation of NF-B is repressed by the product of the viral gene IE86: IE86 appears to block NF-B binding to DNA but not nuclear translocation of NF-B. Intriguingly, IE86 is detectable throughout an infection with the virus, so how UL144 is able to activate NF-B in the presence of continued IE86 expression is unclear. Here we show that although IE86 does repress the UL144-mediated activation of a synthetic NF-B promoter, it is unable to block UL144-mediated activation of the CCL22 promoter, and this lack of responsiveness to IE86 appears to be regulated by binding of the CREB transcription factor.

Published ahead of print on 20 February 2008.