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Journal of Virology, July 2002, p. 6558-6567, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6558-6567.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Differential Effect of Murine Alpha/Beta Interferon Transgenes on Antagonization of Herpes Simplex Virus Type 1 Replication

Peter Härle,1 Vanessa Cull,2 Martin-Paul Agbaga,1 Robert Silverman,3 Bryan R. G. Williams,3 Cassandra James,2 and Daniel J. J. Carr1,4*

Departments of Ophthalmology,1 Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104,4 Division of Veterinary & Biomedical Science, Murdoch University, Perth, Australia 6150,2 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 441953

Received 21 December 2001/ Accepted 5 April 2002

Alpha/beta interferons (IFN-{alpha}/ß) are potent, endogenous antiviral cytokines that suppress the replication of RNA and DNA viruses, including herpes simplex virus type 1 (HSV-1). The present study compared the efficacies of IFN-{alpha}/ß transgenes, including IFN-{alpha}1, -{alpha}4, -{alpha}5, -{alpha}6, -{alpha}9, and -ß, against HSV-1 infection. L929 cells transfected with the IFN-{alpha}/ß transgenes produced similar levels of IFN, as measured by bioassay and enzyme-linked immunosorbent assay. In addition, transfected cells were less susceptible to HSV-1 infection than were cells transfected with a plasmid vector control. The murine IFN-ß plasmid construct exhibited the greatest reduction, while the murine IFN-{alpha}5 transgene showed a modest inhibitory effect in viral titers recovered from the supernatants of transfected, infected L929 cultures. Consistent with this observation, the IFN-ß transgene antagonized viral transcript levels, including infected cell protein 27, thymidine kinase, and glycoprotein B, to a greater extent than did the IFN-{alpha} transgenes at 6 to 10 h postinfection as determined by real-time PCR. Cells transfected with the IFN-{alpha}4, IFN-{alpha}9, or IFN-ß transgenes showed the greatest reduction in viral protein expression relative to the other transfected cells, which was associated with increased STAT1 expression. The absence of the IFN-responsive protein kinase R (PKR) gene completely abrogated the antiviral induction by all IFN-{alpha}/ß against HSV-1. In the absence of RNase L, viral yields were increased 10-fold, but the antiviral effect of IFN was either unaffected or enhanced. These results suggest that the predominant IFN-mediated, antiviral pathway during HSV-1 infection taken by IFN-{alpha}/ß in L929 cells utilizes PKR.

* Corresponding author. Mailing address: Department of Ophthalmology, DMEI no. 415, OUHSC, 608 Stanton L. Young Blvd., Oklahoma City, OK 73104. Phone: (405) 271-1084. Fax: (405) 271-8781. E-mail: dan-carr{at}ouhsc.edu.

Journal of Virology, July 2002, p. 6558-6567, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6558-6567.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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