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陕西快乐十分18.05.14:Hypervariable region 1 and N-linked glycans of hepatitis C regulate virion neutralization by modulating envelope conformations
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Hepatitis C virus (HCV) is a pervasive human pathogen for which a vaccine is urgently needed. Vaccine development relies on inducing neutralizing antibodies (NAbs), but HCV employs complex mechanisms to evade neutralization that remain incompletely understood. Here, we discover a unique interplay between two separate molecular features of HCV envelope protein E2, the hypervariable region 1 and N-linked glycans, that protect HCV from NAbs. Furthermore, we find that they share a mechanism in which they broadly modulate NAb epitope availability by influencing stability of closed and open envelope protein conformations (e.g., envelope breathing) and virus entry dependency on scavenger receptor BI. The apparent importance of structural dynamics in understanding HCV NAb evasion and entry have important implications for rational vaccine design.
About two million new cases of hepatitis C virus (HCV) infections annually underscore the urgent need for a vaccine. However, this effort has proven challenging because HCV evades neutralizing antibodies (NAbs) through molecular features of viral envelope glycoprotein E2, including hypervariable region 1 (HVR1) and N-linked glycans. Here, we observe large variation in the effects of removing individual E2 glycans across HCV strains H77(genotype 1a), J6(2a), and S52(3a) in Huh7.5 cell infections. Also, glycan-mediated effects on neutralization sensitivity were completely HVR1-dependent, and neutralization data were consistent with indirect protection of epitopes, as opposed to direct steric shielding. Indeed, the effect of removing each glycan was similar both in type (protective or sensitizing) and relative strength across four nonoverlapping neutralization epitopes. Temperature-dependent neutralization (e.g., virus breathing) assays indicated that both HVR1 and protective glycans stabilized a closed, difficult to neutralize, envelope conformation. This stabilizing effect was hierarchical as removal of HVR1 fully destabilized closed conformations, irrespective of glycan status, consistent with increased instability at acidic pH and high temperatures. Finally, we observed a strong correlation between neutralization sensitivity and scavenger receptor BI dependency during viral entry. In conclusion, our study indicates that HVR1 and glycans regulate HCV neutralization by shifting the equilibrium between open and closed envelope conformations. This regulation appears tightly linked with scavenger receptor BI dependency, suggesting a role of this receptor in transitions from closed to open conformations during entry. This importance of structural dynamics of HCV envelope glycoproteins has critical implications for vaccine development and suggests that similar phenomena could contribute to immune evasion of other viruses.
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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.
Reviewers: M.J.E., Icahn School of Medicine at Mount Sinai; and R.R., Saint Louis University.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1822002116/-/DCSupplemental.
Published under the PNAS license.