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Journal of Virology, November 2002, p. 11541-11550, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11541-11550.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Alpha/Beta Interferon and Gamma Interferon Synergize To Inhibit the Replication of Herpes Simplex Virus Type 1

Bruno Sainz Jr, and William P. Halford*

Department of Microbiology and Immunology, Tulane University Health Sciences Center, Program in Molecular Pathogenesis and Immunity, New Orleans, Louisiana 70112

Received 23 May 2002/ Accepted 14 August 2002

In vivo evidence suggests that T-cell-derived gamma interferon (IFN-{gamma}) can directly inhibit the replication of herpes simplex virus type 1 (HSV-1). However, IFN-{gamma} is a weak inhibitor of HSV-1 replication in vitro. We have found that IFN-{gamma} synergizes with the innate IFNs (IFN-{alpha} and -ß) to potently inhibit HSV-1 replication in vitro and in vivo. Treatment of Vero cells with either IFN-ß or IFN-{gamma} inhibits HSV-1 replication by <20-fold, whereas treatment with both IFN-ß and IFN-{gamma} inhibits HSV-1 replication by ~1,000-fold. Treatment with IFN-ß and IFN-{gamma} does not prevent HSV-1 entry into Vero cells, and the inhibitory effect can be overcome by increasing the multiplicity of HSV-1 infection. The capacity of IFN-ß and IFN-{gamma} to synergistically inhibit HSV-1 replication is not virus strain specific and has been observed in three different cell types. For two of the three virus strains tested, IFN-ß and IFN-{gamma} inhibit HSV-1 replication with a potency that approaches that achieved by a high dose of acyclovir. Pretreatment of mouse eyes with IFN-ß and IFN-{gamma} reduces HSV-1 replication to nearly undetectable levels, prevents the development of disease, and reduces the latent HSV-1 genome load per trigeminal ganglion by ~200-fold. Thus, simultaneous activation of IFN-{alpha}/ß receptors and IFN-{gamma} receptors appears to render cells highly resistant to the replication of HSV-1. Because IFN-{alpha} or IFN-ß is produced by most cells as an innate response to virus infection, the results imply that IFN-{gamma} secreted by T cells may provide a critical second signal that potently inhibits HSV-1 replication in vivo.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Tulane University Medical School, 1430 Tulane Ave., SL-38, New Orleans, LA 70112. Phone: (504) 988-1376. Fax: (504) 588-5144. E-mail: halford{at}tulane.edu.

Journal of Virology, November 2002, p. 11541-11550, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11541-11550.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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