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J. Virol. doi:10.1128/JVI.01119-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

HERPES SIMPLEX VIRUS TYPE 1 ICP27-DEPENDENT ACTIVATION OF NFB

Department of Microbiology and Immunology, and Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7290, Department of Microbiology, University of Minnesota Medical School, Mayo Mail Code 196, 420 Delaware Street SE, Minneapolis, MN 55455

^* To whom correspondence should be addressed. Email: bachlab{at}med.unc.edu.

	Abstract

The ability of herpes simplex virus type 1 (HSV-1) to activate NFB has been well documented. Beginning at 3-5 h post infection, HSV-1 induces a robust and persistent nuclear translocation of an NFB-dependent (p50/p65 heterodimer) DNA binding activity, as measured by EMSA. Activation requires virus binding and entry, as well as de novo infected cell protein synthesis and is accompanied by loss of both IB and IB. In this study we identified loss of IB as a marker of NFB activation, and infection with mutants deleted for individual immediate-early (IE) regulatory proteins indicated that ICP27 was necessary for IB loss. Analysis of both N-terminal and C-terminal mutants of ICP27 identified the region from aa21-63 as necessary for IB loss. Additional experiments with mutant viruses deleted for combinations of IE genes, revealed that the ICP27-dependent mechanism of NFB activation may be augmented by functional ICP4. We also analyzed two additional markers for NFB activation, phosphorylation of the p65 subunit on ser276 and ser536. Phosphorylation of both serines was induced upon HSV infection, and required functional ICP4 and ICP27. Pharmacological inhibitor studies revealed that both IB and ser276 phosphorylation were dependent on JNK kinase activity, while ser536 phosphorylation was not affected during inhibitor treatment. These results demonstrate that there are several layers of regulation of NFB activation during HSV infection, highlighting the important role that NFB may play in infection.

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