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PLoS Pathog. 2016 Feb 10;12(2):e1005428. doi: 10.1371/journal.ppat.1005428. eCollection 2016 Feb.

The Hepatitis C Virus-Induced Membranous Web and Associated Nuclear Transport Machinery Limit Access of Pattern Recognition Receptors to Viral Replication Sites.

Author information

1
Department of Cell Biology University of Alberta, Edmonton, Alberta, Canada.
2
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
3
Li Ka Shing Institute of Virology, Edmonton, Alberta, Canada.
4
Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
5
Department of Immunology, University of Washington, Seattle, Washington, United States of America.

Abstract

Hepatitis C virus (HCV) is a positive-strand RNA virus of the Flaviviridae family and a major cause of liver disease worldwide. HCV replicates in the cytoplasm, and the synthesis of viral proteins induces extensive rearrangements of host cell membranes producing structures, collectively termed the membranous web (MW). The MW contains the sites of viral replication and assembly, and we have identified distinct membrane fractions derived from HCV-infected cells that contain replication and assembly complexes enriched for viral RNA and infectious virus, respectively. The complex membrane structure of the MW is thought to protect the viral genome limiting its interactions with cytoplasmic pattern recognition receptors (PRRs) and thereby preventing activation of cellular innate immune responses. Here we show that PRRs, including RIG-I and MDA5, and ribosomes are excluded from viral replication and assembly centers within the MW. Furthermore, we present evidence that components of the nuclear transport machinery regulate access of proteins to MW compartments. We show that the restricted assess of RIG-I to the MW can be overcome by the addition of a nuclear localization signal sequence, and that expression of a NLS-RIG-I construct leads to increased immune activation and the inhibition of viral replication.

PMID:
26863439
PMCID:
PMC4749181
DOI:
10.1371/journal.ppat.1005428
[Indexed for MEDLINE]
Free PMC Article

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