This Article Full Text (PDF) Other Versions of this Article: JVI.01168-06v1 80/23/11686    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Montag, C. Articles by Hagemeier, C. Search for Related Content PubMed PubMed Citation Articles by Montag, C. Articles by Hagemeier, C.

 Previous Article  |  Next Article 

J. Virol. doi:10.1128/JVI.01168-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Human Cytomegalovirus blocks TNF and IL-1-mediated NF-B signaling

Laboratory of Molecular Biology, Childrens' Hospital, Charité, Humboldt-University Berlin, Germany

^* To whom correspondence should be addressed. Email: christian.hagemeier{at}charite.de.

	Abstract

NF-B plays an important role in the early cellular response to pathogens by activating genes involved in inflammation, immune response, cell proliferation and survival. NF-B is also utilized by many viral pathogens, like human cytomegalovirus (HCMV), to activate their own gene expression programs, reflecting an intricate role of NF-B both, for anti-viral defense mechanisms and viral physiology. Here we show that the NF-B signaling pathway stimulated by pro-inflammatory cytokines TNF and IL-1 becomes inhibited in HCMV-infected cells. The block to NF-B signaling is first noticeable during the early phase of infection but only fully established at later times. Biochemical and genetic evidence demonstrates that the viral inhibition of pro-inflammatory signaling by distinct cytokines occurs upstream of the convergence point of NF-B activating pathways, i.e. the IB kinase complex and that it is mediated via different mechanisms. Consistent with this, we further show that an HCMV variant that has lost the ability to downregulate TNF-induced NF-B signaling also fails to downregulate surface expression of the TNF receptor 1, thereby mechanistically linking the inhibition of TNF-induced NF-B signaling by HCMV to TNF receptor targeting. Our data support a model whereby HCMV inhibits cytokine-induced NF-B signaling at later times during infection and we suggest that this contributes to the inhibition of the cell's antiviral defense program.

This article has been cited by other articles:

• Wiebusch, L., Neuwirth, A., Grabenhenrich, L., Voigt, S., Hagemeier, C. (2008). Cell Cycle-Independent Expression of Immediate-Early Gene 3 Results in G1 and G2 Arrest in Murine Cytomegalovirus-Infected Cells. J. Virol. 82: 10188-10198 [Abstract] [Full Text]  
• Le, V. T. K., Trilling, M., Zimmermann, A., Hengel, H. (2008). Mouse cytomegalovirus inhibits beta interferon (IFN-{beta}) gene expression and controls activation pathways of the IFN-{beta} enhanceosome. J. Gen. Virol. 89: 1131-1141 [Abstract] [Full Text]  
• Mack, C., Sickmann, A., Lembo, D., Brune, W. (2008). Inhibition of proinflammatory and innate immune signaling pathways by a cytomegalovirus RIP1-interacting protein. Proc. Natl. Acad. Sci. USA 105: 3094-3099 [Abstract] [Full Text]  
• El Mjiyad, N., Bontems, S., Gloire, G., Horion, J., Vandevenne, P., Dejardin, E., Piette, J., Sadzot-Delvaux, C. (2007). Varicella-Zoster Virus Modulates NF-{kappa}B Recruitment on Selected Cellular Promoters. J. Virol. 81: 13092-13104 [Abstract] [Full Text]