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J. Virol. doi:10.1128/JVI.01649-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Independent and cooperative antiviral actions of interferon beta and interferon gamma against Herpes Simplex Virus replication in primary human fibroblasts

Department of Microbiology, School of Medicine, University of Washington; Department of Laboratory Medicine, School of Medicine, University of Washington

^* To whom correspondence should be addressed. Email: rogerb{at}u.washington.edu.

	Abstract

Type I and type II interferons act in synergy to inhibit the replication of a variety of viruses, including Herpes Simplex Virus (HSV). To understand the mechanism of this effect, we have analyzed the transcriptional profiles of primary human fibroblast cells that were first treated with interferon beta (IFNB1), interferon gamma (IFNG), or a combination of both and then subsequently infected with HSV-1. We have identified two types of synergistic activity in the gene expression patterns induced by IFNB1 and IFNG that may contribute to inhibition of HSV-1 replication. The first is defined as "synergy by independent action", in which IFNB1 and IFNG induce distinct gene categories. The second,"synergy by cooperative action", is a term that describes the positive interaction between IFNB1 and IFNG as defined by a 2-way analysis of variance (ANOVA). This form of synergy leads to a much higher level of expression for a subset of genes than is seen with either interferon alone. The cooperatively induced genes by INFB1 and IFNG include those involved in apoptosis, RNA degradation, and inflammatory response. Furthermore, the combination of IFNB1 and IFNG induce significantly more apoptosis and inhibit HSV-1 gene expression and DNA replication significantly more than treatment with each interferon alone. Taken together, these data suggest that IFNB1 and IFNG work both independently and cooperatively to create an antiviral state that synergistically inhibits HSV-1 replication in primary human fibroblasts and that cooperatively induced apoptosis may play a role in the synergistic effect on viral replication.