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Journal of Virology, December 2004, p. 13582-13590, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13582-13590.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Efficient Replication by Herpes Simplex Virus Type 1 Involves Activation of the I{kappa}B Kinase-I{kappa}B-p65 Pathway

D. Gregory,1 D. Hargett,2 D. Holmes,2 E. Money,2 and S. L. Bachenheimer1,2*

Curriculum in Genetics and Molecular Biology,1 Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina2

Received 10 May 2004/ Accepted 28 July 2004

Infection by herpes simplex virus type 1 (HSV-1) induces a persistent nuclear translocation of NF{kappa}B. To identify upstream effectors of NF{kappa}B and their effect on virus replication, we employed mouse embryo fibroblast (MEF)-derived cell lines with deletions of either IKK1 or IKK2, the catalytic subunits of the I{kappa}B kinase (IKK) complex. Infected MEFs were assayed for virus yield, loss of I{kappa}B{alpha}, nuclear translocation of p65, and NF{kappa}B DNA-binding activity. Absence of either IKK1 or IKK2 resulted in an 86 to 94% loss of virus yield compared to that of normal MEFs, little or no loss of I{kappa}B{alpha}, and greatly reduced NF{kappa}B nuclear translocation. Consistent with reduced virus yield, accumulation of the late proteins VP16 and gC was severely depressed. Infection of normal MEFs, Hep2, or A549 cells with an adenovirus vector expressing a dominant-negative (DN) I{kappa}B{alpha}, followed by superinfection with HSV, resulted in a 98% drop in virus yield. These results indicate that the IKK-I{kappa}B-p65 pathway activates NF{kappa}B after virus infection. Analysis of NF{kappa}B activation and virus replication in control and double-stranded RNA-activated protein kinase-null MEFs indicated that this kinase plays no role in the NF{kappa}B activation pathway. Finally, in cells where NF{kappa}B was blocked because of DNI{kappa}B expression, HSV failed to suppress two markers of apoptosis, cell surface Annexin V staining and PARP cleavage. These results support a model in which activation of NF{kappa}B promotes efficient replication by HSV, at least in part by suppressing a host innate response to virus infection.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, 837 MEJB, University of North Carolina, Chapel Hill, NC 27599-7290. Phone: (919) 966-2445. Fax: (919) 962-8103. E-mail: bachlab{at}med.unc.edu.

Journal of Virology, December 2004, p. 13582-13590, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13582-13590.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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