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

Stejskal, L. et al. (2022) An entropic safety catch controls Hepatitis C virus entry and antibody resistance. eLife, 11, e71854. (doi: 10.7554/eLife.71854) (PMID:35796426) (PMCID:PMC9333995)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Grove, Dr Joe and Illingworth, Dr Chris and Gallo, Dr Giulia and Lewis, Miss Charlotte
Authors: Stejskal, L., Kalemera, M. D., Lewis, C. B., Palor, M., Walker, L., Daviter, T., Lees, W. D., Moss, D. S., Kremyda-Vlachou, M., Kozlakidis, Z. Z., Gallo, G., Bailey, D., Rosenberg, W., Illingworth, C. J.R., Shepherd, A. J., and Grove, J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN (Online):2050-084X
Published Online:07 July 2022
Copyright Holders:Copyright © 2022 Stejskal et al.
First Published:First published in eLife 11: e71854
Publisher Policy:Reproduced under a Creative Commons License
Data DOI:10.5281/zenodo.4309544

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
315250MRC PE seed funding - John McLauchlanJohn McLauchlanMedical Research Council (MRC)MC_UU_12014III - Centre for Virus Research