An entropic safety catch controls Hepatitis C virus entry and antibody resistance

  1. Lenka Stejskal
  2. Mphatso D Kalemera
  3. Charlotte B Lewis
  4. Machaela Palor
  5. Lucas Walker
  6. Tina Daviter
  7. William D Lees
  8. David S Moss
  9. Myrto Kremyda-Vlachou
  10. Zisis Zisis Kozlakidis
  11. Giulia Gallo
  12. Dalan Bailey
  13. William Rosenberg
  14. Christopher JR Illingworth
  15. Adrian J Shepherd
  16. Joe Grove  Is a corresponding author
  1. University College London, United Kingdom
  2. University of Glasgow, United Kingdom
  3. Birkbeck, University of London, United Kingdom
  4. World Health Organization, France
  5. The Pirbright Institute, United Kingdom
  6. University of Cambridge, United Kingdom

Abstract

E1 and E2 (E1E2), the fusion proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Thus, HVR-1 is akin to a safety catch that prevents premature triggering of E1E2 activity. Crucially, this mechanism is turned off by host receptor interactions at the cell surface to allow entry. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies. This discovery provides an explanation for the ability of HCV to persist in the face of continual immune assault and represents a novel regulatory mechanism that is likely to be found in other viral fusion machinery.

Data availability

The underlying data for this manuscript are provided as a Source Data file. Full molecular dynamic simulation trajectories are available here: https://zenodo.org/record/4309544

Article and author information

Author details

  1. Lenka Stejskal

    Institute of Immunity and Transplantation, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Mphatso D Kalemera

    Institute of Immunity and Transplantation, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9461-1117
  3. Charlotte B Lewis

    University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Machaela Palor

    Institute of Immunity and Transplantation, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Lucas Walker

    Institute of Immunity and Transplantation, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Tina Daviter

    Institute of Structural and Molecular Biology, Birkbeck, University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. William D Lees

    Institute of Structural and Molecular Biology, Birkbeck, University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. David S Moss

    Institute of Structural and Molecular Biology, Birkbeck, University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Myrto Kremyda-Vlachou

    Division of Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Zisis Zisis Kozlakidis

    International Agency for Research on Cancer, World Health Organization, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Giulia Gallo

    The Pirbright Institute, Pirbright, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Dalan Bailey

    Virus Programme, The Pirbright Institute, Guildford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5640-2266
  13. William Rosenberg

    Institute for Liver and Digestive Health, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2732-2304
  14. Christopher JR Illingworth

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0030-2784
  15. Adrian J Shepherd

    Biological Sciences, Birkbeck, University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0194-8613
  16. Joe Grove

    University of Glasgow, Glasgow, United Kingdom
    For correspondence
    Joe.Grove@glasgow.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5390-7579

Funding

Wellcome Trust (107653/Z/15/Z)

  • Joe Grove

Medical Research Council (MC_UU_12014)

  • Joe Grove

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Fully consented blood samples (for IgG isolation) were collected from HCV+ patients under ethical approval: "Characterising and modifying immune responses in chronic viral hepatitis"; IRAS Number 43993; REC number 11/LO/0421.

Reviewing Editor

  1. Glenn Randall

Publication history

  1. Preprint posted: November 11, 2020 (view preprint)
  2. Received: July 1, 2021
  3. Accepted: June 28, 2022
  4. Accepted Manuscript published: July 7, 2022 (version 1)
  5. Version of Record published: July 28, 2022 (version 2)

Copyright

© 2022, Stejskal et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lenka Stejskal
  2. Mphatso D Kalemera
  3. Charlotte B Lewis
  4. Machaela Palor
  5. Lucas Walker
  6. Tina Daviter
  7. William D Lees
  8. David S Moss
  9. Myrto Kremyda-Vlachou
  10. Zisis Zisis Kozlakidis
  11. Giulia Gallo
  12. Dalan Bailey
  13. William Rosenberg
  14. Christopher JR Illingworth
  15. Adrian J Shepherd
  16. Joe Grove
(2022)
An entropic safety catch controls Hepatitis C virus entry and antibody resistance
eLife 11:e71854.
https://doi.org/10.7554/eLife.71854
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