We elucidate the role of human VH1-69 antibodies in broad neutralization of HCV to facilitate rational vaccine design.

Author contributions: J.P. and J.B. designed research; J.P., R.V.-M., E.H.A., and A.G. performed research; R.W., M.L., and H.A. contributed new reagents/analytic tools; J.P., R.V.-M., E.H.A., A.G., and J.B. analyzed data; and J.P. and J.B wrote the paper.

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.