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

• Published in: eLife Vol. 11
• Main Authors: Stejskal, Lenka, Kalemera, Mphatso D, Lewis, Charlotte B, Palor, Machaela, Walker, Lucas, Daviter, Tina, Lees, William D, Moss, David S, Kremyda-Vlachou, Myrto, Kozlakidis, Zisis, Gallo, Giulia, Bailey, Dalan, Rosenberg, William, Illingworth, Christopher J R, Shepherd, Adrian J, Grove, Joe
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 07-07-2022; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Antibodies; Antibodies, Neutralizing; Cell surface; Cloning; CRISPR; Disease resistance; Entropy; Experiments; Gene deletion; Glycoproteins; Hepacivirus - genetics; Hepacivirus - metabolism; Hepatitis; Hepatitis C; Hepatitis C virus; Humans; Infections; Microbiology and Infectious Disease; molecular dynamics; Molecular modelling; Mutation; protein disorder; Proteins; Safety; Safety and security measures; Structural Biology and Molecular Biophysics; Vaccines; Viral antibodies; Viral Envelope Proteins - metabolism; Virions; virus entry; Virus Internalization; Viruses; Canada; hepatitis c virus; viruses; infectious disease; microbiology; virus entry; antibodies; structural biology; molecular biophysics; molecular dynamics; protein disorder
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.71854

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.