ArticleHepatology (Baltimore, Md.)2016
Hypervariable region 1 shielding of hepatitis C virus is a main contributor to genotypic differences in neutralization sensitivity.
Article in Hepatology (Baltimore, Md.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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57 citing papers in PubMed, 76 citations in OpenAlex.
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- Antibody responses to a highly conserved peptide in HCV E2 protein correlate with chronicity or spontaneous clearance of HCV infection.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Fine-tuning of hepatitis C virus immune evasion through hypervariable region 1 insertions.Hepatology (Baltimore, Md.) · 2025Article
- Cryo-EM structures of HCV E2 glycoprotein bound to neutralizing and non-neutralizing antibodies determined using bivalent Fabs as fiducial markers.Communications biology · 2025Article
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- 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
- Hepatitis C virus hypervariable region 1 antibodies interrupt E2-SR-B1 interaction to suppress viral infection.iScience · 2023Article
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- Two-component vaccine consisting of virus-like particles displaying hepatitis C virus envelope protein 2 oligomers.NPJ vaccines · 2022Article
- Novel HCV Genotype 4d Infectious Systems and Assessment of Direct-Acting Antivirals and Antibody Neutralization.Viruses · 2022Article
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- Structural perspectives on HCV humoral immune evasion mechanisms.Current opinion in virology · 2021Review
- Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial.Viruses · 2021Review
- In vitro adaptation and characterization of attenuated hypervariable region 1 swap chimeras of hepatitis C virus.PLoS pathogens · 2021Article
- Hepatitis C Virus Glycan-Dependent Interactions and the Potential for Novel Preventative Strategies.Pathogens (Basel, Switzerland) · 2021Review
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5 authors at 4 institutions in 2 countries.
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Abstract
There are 3-4 million new hepatitis C virus (HCV) infections yearly. The extensive intergenotypic sequence diversity of envelope proteins E1 and E2 of HCV and shielding of important epitopes by hypervariable region 1 (HVR1) of E2 are believed to be major hindrances to developing universally protective HCV vaccines. Using cultured viruses expressing the E1/E2 complex of isolates H77 (genotype 1a), J6 (2a), or S52 (3a), with and without HVR1, we tested HVR1-mediated neutralization occlusion in vitro against a panel of 12 well-characterized human monoclonal antibodies (HMAbs) targeting diverse E1, E2, and E1/E2 epitopes. Surprisingly, HVR1-mediated protection was greatest for S52, followed by J6 and then H77. HCV pulldown experiments showed that this phenomenon was caused by epitope shielding. Moreover, by regression analysis of HMAb binding and neutralization titer of HCV we found a strong correlation for HVR1-deleted viruses but not for parental viruses retaining HVR1. The intergenotype neutralization sensitivity of the parental viruses to HMAb antigenic region (AR) 2A, AR3A, AR4A, AR5A, HC84.26, and HC33.4 varied greatly (>24-fold to >130-fold differences in 50% inhibitory concentration values). However, except for AR5A, these differences decreased to less than 6.0-fold when comparing the corresponding HVR1-deleted viruses. Importantly, this simplified pattern of neutralization sensitivity in the absence of HVR1 was also demonstrated in a panel of HVR1-deleted viruses of genotypes 1a, 2a, 2b, 3a, 5a, and 6a, although for all HMAbs, except AR4A, an outlier was observed. Finally, unique amino acid residues in HCV E2 could explain these outliers in the tested cases of AR5A and HC84.26.
conclusionHVR1 adds complexity to HCV neutralization by shielding a diverse array of unexpectedly cross-genotype-conserved E1/E2 epitopes. Thus, an HVR1-deleted antigen could be a better HCV vaccine immunogen. (Hepatology 2016;64:1881-1892).
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