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HSV-1-Induced SOCS-1 Expression in Keratinocytes: Use of a SOCS-1 Antagonist to Block a Novel Mechanism of Viral Immune Evasion¹

Kenneth G. Frey^*, Chulbul M. I. Ahmed, Rea Dabelic, Lindsey D. Jager, Ezra N. Noon-Song, S. Mohammad Haider, Howard M. Johnson and Nancy J. Bigley^2,*,

^* Department of Neuroscience, Cell Biology, and Physiology and Department of Pathology, Wright State University, Dayton, OH 45435; and Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611

Keratinocytes are important for the acute phase of HSV-1 infection and subsequent persistence in sensory nervous tissue. In this study, we showed that keratinocytes (HEL-30) were refractory to IFN- induction of an antiviral state to HSV-1 infection, while IFN- did induce an antiviral state in fibroblasts (L929). This led us to examine the possible role of suppressor of cytokine signaling-1 (SOCS-1) in this refractiveness. RT-PCR analysis of SOCS-1 mRNA expression in HSV-1-infected cells showed a 4-fold increase for keratinocytes while having a negligible effect on fibroblasts. A similar pattern was observed at the level of SOCS-1 protein induction. Activation of STAT1 in keratinocytes was inhibited by HSV-1 infection. A direct effect of HSV-1 on the SOCS-1 promoter was shown in a luciferase reporter gene assay. We have developed a small peptide antagonist of SOCS-1, pJAK2(1001–1013), that had both an antiviral effect in keratinocytes against HSV-1 as well as a synergistic effect on IFN- induction of an antiviral state. HSV-1 ICP0 mutant was inhibited by IFN- in HEL-30 cells and was less effective than wild-type virus in induction of SOCS-1 promoter. We conclude that SOCS-1 plays an important role in the inhibition of the antiviral effect of IFN- in keratinocytes infected with HSV-1. The use of SOCS-1 antagonist to abrogate this refractiveness could have a transformational effect on therapy against viral infections.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grants 5R01NS51245 and 2R01AI056152 (to H.M.J.), Wright State University Research Foundation, Cellular Immunology Fund 550527 (to N.J.B.), and Sigma Xi Grant in Aid of Research (to K.G.F.).

² Address correspondence and reprint requests to Dr. Nancy J. Bigley, Department of Neuroscience, Cell Biology, and Physiology and Department of Pathology, Wright State University, Dayton, OH 45435. E-mail address: nancy.bigley{at}wright.edu

³ Abbreviations used in this paper: SOCS, suppressor of cytokine signaling; CPE, cytopathic effect; KIR, kinase inhibitory region; moi, multiplicity of infection; siRNA, small interfering RNA; Tkip, tyrosine kinase inhibitor peptide.