An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance

• DOI: 10.1101/2020.11.11.377218
• Publication Date: 2020-11-12T08:15:35Z
• Authors: Lenka Stejskal; Mphatso D. Kalemera; Machaela Palor; Lucas Walker; Tina Daviter; William D. Lees; David S. Moss; Myrto Kremyda-Vla...; Zisis Kozlakidis; William Rosenberg; Christopher J. R....; Adrian J. Shepherd; Joe Grove
• Keywords: Hypervariable region; Entry inhibitor

E1 and E2 (E1E2), the entry proteins of Hepatitis C Virus (HCV), are unlike that any other virus yet described, detailed molecular mechanisms HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) is a putative intrinsically disordered protein tail. Here, we demonstrate HVR-1 has an autoinhibitory function suppresses activity E1E2 on free virions; this dependent its conformational entropy. Crucially, to allow entry, mechanism turned off by host receptor interactions at cell surface. Thus, akin safety catch activity. Mutations reduce entropy in HVR-1, or genetic deletion turn generate hyper-reactive exhibits enhanced but thermally unstable acutely sensitive neutralising antibodies. Therefore, controls efficiency maintains resistance