An entropic safety catch controls Hepatitis C virus entry and antibody resistance
- University College London, United Kingdom
- University of Glasgow, United Kingdom
- Birkbeck, University of London, United Kingdom
- World Health Organization, France
- The Pirbright Institute, United Kingdom
- 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
Mphatso D Kalemera
Christopher JR Illingworth
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.
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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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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