The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A

Karla J. Helbig, Nicholas S. Eyre, Evelyn Yip, Sumudu Narayana, Kui Li, Guillaume Fiches, Erin M. Mccartney, Rohit Jangra, Stanley M. Lemon, Michael R. Beard

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

The interferon-stimulated gene, viperin, has been shown to have antiviral activity against hepatitis C virus (HCV) in the context of the HCV replicon, although the molecular mechanisms responsible are not well understood. Here, we demonstrate that viperin plays an integral part in the ability of interferon to limit the replication of cell-culture-derived HCV (JFH-1) that accurately reflects the complete viral life cycle. Using confocal microscopy and fluorescence resonance energy transfer (FRET) analysis, we demonstrate that viperin localizes and interacts with HCV nonstructural protein 5A (NS5A) at the lipid-droplet (LD) interface. In addition, viperin also associates with NS5A and the proviral cellular factor, human vesicle-associated membrane protein-associated protein subtype A (VAP-A), at the HCV replication complex. The ability of viperin to limit HCV replication was dependent on residues within the C-terminus, as well as an N-terminal amphipathic helix. Removal of the amphipathic helix-redirected viperin from the cytosolic face of the endoplasmic reticulum and the LD to a homogenous cytoplasmic distribution, coinciding with a loss of antiviral effect. C-terminal viperin mutants still localized to the LD interface and replication complexes, but did not interact with NS5A proteins, as determined by FRET analysis. Conclusion: In conclusion, we propose that viperin interacts with NS5A and the host factor, VAP-A, to limit HCV replication at the replication complex. This highlights the complexity of the host control of viral replication by interferon-stimulated gene expression.

Original languageEnglish (US)
Pages (from-to)1506-1517
Number of pages12
JournalHepatology
Volume54
Issue number5
DOIs
StatePublished - Nov 2011
Externally publishedYes

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Virus Replication
Hepacivirus
Antiviral Agents
Interferons
Fluorescence Resonance Energy Transfer
Proteins
Integration Host Factors
R-SNARE Proteins
Replicon
Life Cycle Stages
Confocal Microscopy
Endoplasmic Reticulum
Cell Culture Techniques
Gene Expression
Genes
Lipid Droplets

ASJC Scopus subject areas

  • Hepatology

Cite this

Helbig, K. J., Eyre, N. S., Yip, E., Narayana, S., Li, K., Fiches, G., ... Beard, M. R. (2011). The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A. Hepatology, 54(5), 1506-1517. https://doi.org/10.1002/hep.24542

The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A. / Helbig, Karla J.; Eyre, Nicholas S.; Yip, Evelyn; Narayana, Sumudu; Li, Kui; Fiches, Guillaume; Mccartney, Erin M.; Jangra, Rohit; Lemon, Stanley M.; Beard, Michael R.

In: Hepatology, Vol. 54, No. 5, 11.2011, p. 1506-1517.

Research output: Contribution to journalArticle

Helbig, KJ, Eyre, NS, Yip, E, Narayana, S, Li, K, Fiches, G, Mccartney, EM, Jangra, R, Lemon, SM & Beard, MR 2011, 'The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A', Hepatology, vol. 54, no. 5, pp. 1506-1517. https://doi.org/10.1002/hep.24542
Helbig, Karla J. ; Eyre, Nicholas S. ; Yip, Evelyn ; Narayana, Sumudu ; Li, Kui ; Fiches, Guillaume ; Mccartney, Erin M. ; Jangra, Rohit ; Lemon, Stanley M. ; Beard, Michael R. / The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A. In: Hepatology. 2011 ; Vol. 54, No. 5. pp. 1506-1517.
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