TY - JOUR
T1 - Global and local envelope protein dynamics of hepatitis C virus determine broad antibody sensitivity
AU - Augestad, Elias H.
AU - Castelli, Matteo
AU - Clementi, Nicola
AU - Ströh, Luisa J.
AU - Krey, Thomas
AU - Burioni, Roberto
AU - Mancini, Nicasio
AU - Bukh, Jens
AU - Prentoe, Jannick
N1 - Publisher Copyright:
© 2020 The Authors, some rights reserved.
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85090873171&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abb5938
DO - 10.1126/sciadv.abb5938
M3 - Journal articles
C2 - 32923643
AN - SCOPUS:85090873171
SN - 2375-2548
VL - 6
JO - Science Advances
JF - Science Advances
IS - 35
M1 - eabb5938
ER -