Inhibition of interferon signaling by dengue virus

doi:10.1073/pnas.2335168100

Inhibition of interferon signaling by dengue virus

Department of Microbiology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029

Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY (received for review August 12, 2003)

Abstract

Dengue virus is a worldwide-distributed mosquito-borne flavivirus with a positive strand RNA genome. Its transcribed polyprotein is cleaved by host- and virus-encoded peptidases into 10 proteins, some of which are of unknown function. Although dengue virus-infected cells seem to be resistant to the antiviral action of IFN, the viral products that mediate this resistance are unknown. Therefore, we have analyzed the ability of the 10 dengue virus-encoded proteins to antagonize the IFN response. We found that expression in human A549 cells of the dengue virus nonstructural proteins NS2A, NS4A, or NS4B enhances replication of an IFN-sensitive virus. Moreover, expression of NS4B and, to a lesser extent, of NS2A and NS4A proteins results in down-regulation of IFN-β-stimulated gene expression. Cells expressing NS4B or infected with dengue virus do not exhibit nuclear signal transducer and activator of transcription (STAT) 1 on treatment with IFN-β or IFN-γ, indicating that NS4B might be involved in blocking IFN signaling during dengue virus infections. This protein, encoded by a positive strand RNA virus, is implicated as an IFN-signaling inhibitor.

Footnotes

↵ * To whom correspondence should be addressed. E-mail: adolfo.garcia-sastre{at}mssm.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: DEN, dengue virus; ISRE, IFN-stimulated response element; FL, firefly luciferase; NDV, Newcastle disease virus; RL, Renilla luciferase; SeV, Sendai virus; STAT, signal transducer and activator of transcription; ER, endoplasmic reticulum; IRF, IFN regulatory factor; JAK, Janus kinase; HCV, hepatitis C virus; HA, hemagglutinin; CAT, chloramphenicol acetyl transferase; TNF, tumor necrosis factor; CEF, chicken embryo fibroblast.