The Hepatitis C Virus-Induced Membranous Web and Associated Nuclear Transport Machinery Limit Access of Pattern Recognition Receptors to Viral Replication Sites: e1005428

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 m...

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Bibliographic Details
Published in:PLoS pathogens 2016-02, Vol.12 (2)
Main Authors: Neufeldt, Christopher J, Joyce, Michael A, Buuren, Nicholas Van, Levin, Aviad, Kirkegaard, Karla, Jr, Michael Gale, Tyrrell, D LorneJ, Wozniak, Richard W
Format: Article
Language:English
Subjects:
Cytoplasm
Deoxyribonucleic acid
DNA
Flaviviridae
Genomes
Hepatitis
Hepatitis C virus
HIV
Human immunodeficiency virus
Infections
Liver diseases
Localization
Machinery
Membranes
Microscopy
Pattern recognition
Proteins
Viruses
West Nile virus
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Summary: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.
ISSN:1553-7366
1553-7374
DOI:10.1371/journal.ppat.1005428