Global and local envelope protein dynamics of hepatitis C virus determine broad antibody sensitivity

• Published in: Science advances Vol. 6; no. 35; p. eabb5938
• Main Authors: Augestad, Elias H, Castelli, Matteo, Clementi, Nicola, Ströh, Luisa J, Krey, Thomas, Burioni, Roberto, Mancini, Nicasio, Bukh, Jens, Prentoe, Jannick
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.08.2020
• Subjects: Antibodies, Neutralizing; Hepacivirus - genetics; Hepatitis C; Hepatitis C Antibodies; Humans; Immunology; SciAdv r-articles; Viral Envelope Proteins - metabolism; Virology
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abb5938

Broad antibody sensitivity differences of hepatitis C virus (HCV) isolates and their ability to persist in the presence of neutralizing antibodies (NAbs) remain poorly understood. Here, we show that polymorphisms within glycoprotein E2, including hypervariable region 1 (HVR1) and antigenic site 412 (AS412), broadly affect NAb sensitivity by shifting global envelope protein conformation dynamics between theoretical "closed," neutralization-resistant and "open," neutralization-sensitive states. The conformational space of AS412 was skewed toward β-hairpin-like conformations in closed states, which also depended on HVR1, assigning function to these enigmatic E2 regions. Scavenger receptor class B, type I entry dependency of HCV was associated with NAb resistance and correlated perfectly with decreased virus propensity to interact with HCV co-receptor CD81, indicating that decreased NAb sensitivity resulted in a more complex entry pathway. This link between global E1/E2 states and functionally distinct AS412 conformations has important implications for targeting AS412 in rational HCV vaccine designs.