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

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

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 B (NF-B) after infection of fibroblast and macrophage cells. NF-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-B in transient-transfection assays. Here we investigate whether the NF-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-B-alpha (IBM) 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-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-B pathway and binding of NF-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.

C.A.B. and A.A. contributed equally to this work.

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