An entropic safety catch controls hepatitis C virus entry and antibody resistance
Lenka Stejskal,
Mphatso D Kalemera,
Charlotte B Lewis,
Machaela Palor,
Lucas Walker,
Tina Daviter,
William D Lees,
David S Moss,
Myrto Kremyda-Vlachou,
Zisis Kozlakidis,
Giulia Gallo,
Dalan Bailey,
William Rosenberg,
Christopher JR Illingworth,
Adrian J Shepherd,
Joe Grove
Affiliations
Lenka Stejskal
Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom; Institute of Structural and Molecular Biology, Birkbeck College, London, United Kingdom
Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom
Charlotte B Lewis
MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
Machaela Palor
Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom
Lucas Walker
Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom
Tina Daviter
Institute of Structural and Molecular Biology, Birkbeck College, London, United Kingdom; Shared Research Facilities, The Institute of Cancer Research, London, United Kingdom
William D Lees
Institute of Structural and Molecular Biology, Birkbeck College, London, United Kingdom
David S Moss
Institute of Structural and Molecular Biology, Birkbeck College, London, United Kingdom
Myrto Kremyda-Vlachou
Division of Infection and Immunity, University College London, London, United Kingdom
Zisis Kozlakidis
International Agency for Research on Cancer, World Health Organization, Lyon, France
Giulia Gallo
The Pirbright Institute, Pirbright, United Kingdom
MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom; Department of Genetics, University of Cambridge, Cambridge, United Kingdom; Institut für Biologische Physik, Universität zu Köln, Cologne, Germany; MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom
Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
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.