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Type I interferon rapidly restricts infectious hepatitis C virus particle genesis

Meredith, Luke W.; Farquhar, Michelle J.; Tarr, Alexander W.; McKeating, Jane A.

Authors

Luke W. Meredith

Michelle J. Farquhar

Alexander W. Tarr

Jane A. McKeating



Abstract

Interferon-alpha (IFNα) has been used to treat chronic hepatitis C virus (HCV) infection for over 20 years with varying efficacy, depending on the infecting viral genotype. The mechanism of action of IFNα is not fully understood, but is thought to target multiple stages of the HCV lifecycle, inhibiting viral transcription and translation leading to a degradation of viral RNA and protein expression in the infected cell. IFNα induces the expression of an array of interferon-stimulated genes within minutes of receptor engagement; however, the impact of these early responses on the viral lifecycle are unknown. We demonstrate that IFNα inhibits the genesis of infectious extracellular HCV particles within 2 hours of treating infected cells, with minimal effect on the intracellular viral burden. Importantly, this short duration of IFNα treatment of infected cells significantly reduced cell-free and cell-to-cell dissemination. The secreted viral particles showed no apparent change in protein content or density, demonstrating that IFNα inhibits particle infectivity but not secretion rates. To investigate whether particles released from IFNα-treated cells have a reduced capacity to establish infection we used HCV lentiviral pseudotypes (HCVpp) and demonstrated a defect in cell entry. Using a panel of monoclonal antibodies targeting the E2 glycoprotein, we demonstrate that IFNα alters glycoprotein conformation and receptor utilization. Conclusion: These observations show a previously unreported and rapid effect of IFNα on HCV particle infectivity that inhibits de novo infection events. Evasion of this response may be a contributing factor in whether a patient achieves early or rapid virological response, a key indicator of progression to sustained virological response or clearance of viral infection. (Hepatology 2014;60:1890–1900)

Journal Article Type Article
Publication Date Nov 24, 2014
Journal Hepatology
Print ISSN 0270-9139
Electronic ISSN 1527-3350
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 60
Issue 6
APA6 Citation Meredith, L. W., Farquhar, M. J., Tarr, A. W., & McKeating, J. A. (2014). Type I interferon rapidly restricts infectious hepatitis C virus particle genesis. Hepatology, 60(6), https://doi.org/10.1002/hep.27333
DOI https://doi.org/10.1002/hep.27333
Publisher URL https://doi.org/10.1002/hep.27333
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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