title: Hypervariable region 1 shielding of hepatitis C virus is a main contributor to genotypic differences in neutralization sensitivity.
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.
  
  
  
  HVR1 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).
authors.affiliation: Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jannick
authors.initials: J
authors.lastname: Prentoe
authors.affiliation: Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Velázquez-Moctezuma
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Steven K H
authors.initials: SK
authors.lastname: Foung
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA.
authors.forename: Mansun
authors.initials: M
authors.lastname: Law
authors.affiliation: Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Bukh
mesh_terms: D000939:Epitopes / Q000276:immunology; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D009500:Neutralization Tests; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D000939:Epitopes; C400562:HVR1 protein, Hepatitis C virus; D014764:Viral Proteins