ArticleProceedings of the National Academy of Sciences of the United States of America2019
Hypervariable region 1 and N-linked glycans of hepatitis C regulate virion neutralization by modulating envelope conformations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 56 citations in OpenAlex.
- Structure-based design of stable recombinant hepatitis C virus E1E2 heterodimers.Nature communications · 2026Article
- Mapping Determinants of Hepatitis C Virus E1/E2 Transmembrane Interactions Using Intergenotypic Chimeras.Viruses · 2026Article
- In Vivo Determinants of Hepatitis C Virus Adaptation and Escape From Neutralizing Antibody AR5A.Cellular and molecular gastroenterology and hepatology · 2026Article
- Consistent Induction of Broadly Neutralizing HIV Antibodies by a Novel Two-Step Mechanism Informs Immunogen Design.bioRxiv : the preprint server for biology · 2025Article
- Broadly Neutralizing Antibody Characteristics in Hepatitis C Virus Infection and Implications for Vaccine Design.Vaccines · 2025Review
- Cryo-EM structures of HCV E2 glycoprotein bound to neutralizing and non-neutralizing antibodies determined using bivalent Fabs as fiducial markers.Communications biology · 2025Article
- Bispecific antibodies against the hepatitis C virus E1E2 envelope glycoprotein.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Selection and characterization of a broadly neutralizing class of HCV anti-E2 VH1-69 antibodies.PLoS pathogens · 2025Article
- Update on Hepatitis C Vaccine: Results and Challenges.Viruses · 2024Review
- Alterations in N-glycosylation of HCV E2 Protein in Children Patients with IFN-RBV Therapy Failure.Pathogens (Basel, Switzerland) · 2024Article
- Full-length sequence analysis of hepatitis C virus genotype 3b strains and development of anJournal of virology · 2023Article
- N-Linked Glycosylation and Expression of Duck Plague Virus pUL10 Promoted by pUL49.5.Microbiology spectrum · 2023Article
- Signatures of VNature communications · 2023Article
- Polyvalent immunization elicits a synergistic broadly neutralizing immune response to hypervariable region 1 variants of hepatitis C virus.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Current Hepatitis C Vaccine Candidates Based on the Induction of Neutralizing Antibodies.Viruses · 2023Review
- Article
- Two-component vaccine consisting of virus-like particles displaying hepatitis C virus envelope protein 2 oligomers.NPJ vaccines · 2022Article
- Structure of the hepatitis C virus E1E2 glycoprotein complex.Science (New York, N.Y.) · 2022Article
- Article
- Modified E2 Glycoprotein of Hepatitis C Virus Enhances Proinflammatory Cytokines and Protective Immune Response.Journal of virology · 2022Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
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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