1 Dengue virus inhibits interferon-α signaling by reducing

2 Type 1 interferons (IFN-α/β) are key mediators of innate antiviral responses but have little effect on 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 insight into disease pathogenesis. In a recent study analyzing the ability of individual dengue virus-encoded proteins to antagonize the IFN response, non-structural (NS) protein 4B, and possibly NS2A and NS4A, were identified as candidate IFN antagonists. In monkey cells, NS4B appeared to inhibit both IFN-α/β and IFN-γ signal transduction pathways, which are distinct but overlapping (Munoz-Jordan, J. L., G. G. Sanchez-Burgos, M. Laurent-Rolle, and A. Garcia-Sastre. 2003. Proc Natl Acad Sci U S A 100:14333-8). Here we examine the effects of dengue on the human IFN system using cell lines that are stably transfected with self-replicating subgenomic dengue RNA (replicons) and express all the dengue non-structural proteins together. We show tha