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Journal of Virology, January 2004, p. 741-750, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.741-750.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Neutrality of the Canonical NF-{kappa}B-Dependent Pathway for Human and Murine Cytomegalovirus Transcription and Replication In Vitro

Chris A. Benedict,1,{dagger}* Ana Angulo,2,{dagger} Ginelle Patterson,1 Sukwon Ha,1 Huang Huang,3 Martin Messerle,4 Carl F. Ware,1 and Peter Ghazal3,5*

La Jolla Institute of Allergy and Immunology, San Diego, California 92007,1 The Scripps Research Institute, La Jolla, California 92037,3 Institut d'Investigacions Biomediques August Pi i Sunyer, 08036 Barcelona, Spain,2 Virus Cell Interaction Group, Medical Faculty, University of Halle, 06120 Halle, Germany,4 Scottish Centre for Genomic Technology and Informatics, University of Edinburgh Medical School, Edinburgh EH16 4SB, United Kingdom5

Received 18 July 2003/ Accepted 26 September 2003

Cytomegalovirus (CMV) is known to rapidly induce activation of nuclear factor {kappa}B (NF-{kappa}B) after infection of fibroblast and macrophage cells. NF-{kappa}B response elements are present in the enhancer region of the CMV major immediate-early promoter (MIEP), and activity of the MIEP is strongly upregulated by NF-{kappa}B in transient-transfection assays. Here we investigate whether the NF-{kappa}B-dependent pathway is required for initiating or potentiating human and murine CMV replication in vitro. We show that expression of a dominant negative mutant of the inhibitor of NF-{kappa}B-alpha (I{kappa}B{alpha}M) does not alter the replication kinetics of human or mouse CMV in cultured cells. In addition, mouse embryo fibroblasts genetically deficient for p65/RelA actually showed elevated levels of MCMV replication. Mutation of all NF-{kappa}B response elements within the enhancer of the MIEP in a recombinant mouse CMV containing the human MIEP (hMCMV-ES), which we have previously shown to replicate in murine fibroblasts with kinetics equivalent to that of wild-type mouse CMV, did not negatively affect replication in fibroblasts. Taken together, these data show that, for CMV replication in cultured fibroblasts activation of the canonical NF-{kappa}B pathway and binding of NF-{kappa}B to the MIEP are dispensable, and in the case of p65 may even interfere, thus uncovering a previously unrecognized level of complexity in the host regulatory network governing MIE gene expression in the context of a viral infection.

* Corresponding author. Mailing address for Chris Benedict: La Jolla Institute for Allergy and Immunology, Division of Molecular Immunology, 10355 Science Center Dr., San Diego, CA 92007. Phone: (858) 678-4652. Fax: (858) 558-3525. E-mail: benedict{at}liai.org. Mailing address for Peter Ghazal: The Scottish Centre for Genomic Technology and Informatics, University of Edinburgh Medical School, Little France Crescent, Edinburgh EH16 4SB, United Kingdom. Phone: 44-131-242-6288. Fax: 44-131-242-6244. E-mail: p.ghazal{at}ed.ac.uk.

{dagger} C.A.B. and A.A. contributed equally to this work.

Journal of Virology, January 2004, p. 741-750, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.741-750.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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