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)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• 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: 2050-084X
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
315250		MRC PE seed funding - John McLauchlan	John McLauchlan	Medical Research Council (MRC)	MC_UU_12014	III - Centre for Virus Research