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J. Biol. Chem., Vol. 281, Issue 11, 7110-7117, March 17, 2006

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Herpes Simplex Virus Disrupts NF-B Regulation by Blocking Its Recruitment on the IB Promoter and Directing the Factor on Viral Genes^*

Carla Amici¹, Antonio Rossi¹, Antonio Costanzo^¶1, Stefania Ciafrè, Barbara Marinari^¶2, Mirna Balsamo, Massimo Levrero^||, and M. Gabriella Santoro³

From the Department of Biology and ^¶Dermatology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, the Institute of Neurobiology and Molecular Medicine, CNR, 00133 Rome, and the ^||Department of Internal Medicine, University of Rome La Sapienza, 00185 Rome, Italy

Herpes simplex viruses (HSVs) are able to hijack the host-cell IB kinase (IKK)/NF-B pathway, which regulates critical cell functions from apoptosis to inflammatory responses; however, the molecular mechanisms involved and the outcome of the signaling dysregulation on the host-virus interaction are mostly unknown. Here we show that in human keratinocytes HSV-1 attains a sophisticated control of the IKK/NF-B pathway, inducing two distinct temporally controlled waves of IKK activity and disrupting the NF-B autoregulatory mechanism. Using chromatin immunoprecipitation we demonstrate that dysregulation of the NF-B-response is mediated by a virus-induced block of NF-B recruitment to the promoter of the IB gene, encoding the main NF-B-inhibitor. We also show that HSV-1 redirects NF-B recruitment to the promoter of ICP0, an immediate-early viral gene with a key role in promoting virus replication. The results reveal a new level of control of cellular functions by invading viruses and suggest that persistent NF-B activation in HSV-1-infected cells, rather than being a host response to the virus, may play a positive role in promoting efficient viral replication.

Received for publication, November 17, 2005 , and in revised form, December 29, 2005.

^* This work was supported in part by the Italian Ministry of University (Fondi per gli Investimenti della Ricerca di Base projects) (to M. G. S. and M. L.) and by the Italian Ministry of Public Health (Istituto Superiore di Sanità project: Eziopatogenesi e Studi Immunologici e Virologici dell'HIV/AIDS) (to M. G. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Supported by a Fondazione Italiana per la Ricerca sul Cancro fellowship.

³ To whom correspondence should be addressed. Tel.: 39-06-7259-4822; Fax: 39-06-7259-4821; E-mail: santoro{at}bio.uniroma2.it.

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