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Dengue Virus Inhibits Alpha Interferon Signaling by Reducing STAT2 Expression

DDRC, Queen Mary's School of Medicine and Dentistry,¹ Centre for Hepatology, Royal Free & University College Medical School, London,⁴ Department of Pathology and Microbiology, University of Bristol, Bristol, United Kingdom,² Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany³

Received 16 August 2004/ Accepted 10 December 2004

Alpha/beta interferon (IFN-/ß) is a key mediator of innate antiviral responses but has little effect on the established replication of dengue viruses, which are mosquito-borne flaviviruses of immense global health importance. Understanding how the IFN system is inhibited in dengue virus-infected cells would provide critical insights into disease pathogenesis. In a recent study analyzing the ability of individual dengue virus-encoded proteins to antagonize the IFN response, nonstructural (NS) protein 4B and possibly NS2A and NS4A were identified as candidate IFN antagonists. In monkey cells, NS4B appeared to inhibit both the IFN-/ß and IFN- signal transduction pathways, which are distinct but overlapping (J. L. Munoz-Jordan, G. G. Sanchez-Burgos, M. Laurent-Rolle, and A. Garcia-Sastre, Proc. Natl. Acad. Sci. USA 100:14333-14338, 2003). For this study, we examined the effects of dengue virus on the human IFN system, using cell lines that were stably transfected with self-replicating subgenomic dengue virus RNA (replicons) and that expressed all of the dengue virus nonstructural proteins together. We show here that in replicon-containing cells dengue virus RNA replication and the replication of encephalomyocarditis virus, an IFN-sensitive virus, are resistant to the antiviral effects of IFN-. The presence of dengue virus replicons reduces global IFN--stimulated gene expression and specifically inhibits IFN- but not IFN- signal transduction. In cells containing replicons or infected with dengue virus, we found reduced levels of signal transducer and activator of transcription 2 (STAT2), which is a key component of IFN- but not IFN- signaling. Collectively, these data show that dengue virus is capable of subverting the human IFN response by down-regulating STAT2 expression.

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