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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 Evasion

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^*,

^*Department of Neuroscience, Cell Biology, and Physiology 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.

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