Global mapping of antibody recognition of the hepatitis C virus E2 glycoprotein: Implications for vaccine design


Abstract

The E2 envelope glycoprotein is the primary target of human neutralizing antibody response against hepatitis C virus (HCV), and is thus a major focus of vaccine and immunotherapeutics efforts. There is emerging evidence that E2 is a highly complex, dynamic protein with residues across the protein that are modulating antibody recognition, local and global E2 stability, and viral escape. To comprehensively map these determinants, we performed global E2 alanine scanning with a panel of 16 human monoclonal antibodies (hmAbs), resulting in an unprecedented dataset of the effects of individual alanine substitutions across the E2 protein (355 positions) on antibody recognition. Analysis of shared energetic effects across the antibody panel identified networks of E2 residues involved in antibody recognition and local and global E2 stability, as well as predicted contacts between residues across the entire E2 protein. Further analysis of antibody binding hotspot residues defined groups of residues essential for E2 conformation and recognition for all 14 conformationally dependent E2 antibodies and subsets thereof, as well as residues that enhance antibody recognition when mutated to alanine, providing a potential route to engineer E2 vaccine immunogens. By incorporating E2 sequence variability, we found a number of E2 polymorphic sites that are responsible for loss of neutralizing antibody binding. These data and analyses provide fundamental insights into antibody recognition of E2, highlighting the dynamic and complex nature of this viral envelope glycoprotein, and can serve as a reference for development and rational design of E2-targeting vaccines and immunotherapeutics.

Submission Details

ID: qhWKngVT4

Submitter: Connie Wang

Submission Date: July 31, 2017, 11:46 a.m.

Version: 1

Publication Details
Pierce BG;Keck ZY;Lau P;Fauvelle C;Gowthaman R;Baumert TF;Fuerst TR;Mariuzza RA;Foung SK,Proc Natl Acad Sci U S A (2016) Global mapping of antibody recognition of the hepatitis C virus E2 glycoprotein: Implications for vaccine design. PMID:27791171
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
5VXR 2017-05-24T00:00:00+0000 1.4 The antigen-binding fragment of MAb24 in complex with a peptide from Hepatitis C Virus E2 epitope I (412-423)
4GAG 2012-07-25T00:00:00+0000 1.8 Structure of the broadly neutralizing antibody AP33 in complex with its HCV epitope (E2 residues 412-423)
2KNU 2009-09-04T00:00:00+0000 0 Solution structure of the transmembrane proximal region of the hepatis C virus E1 glycoprotein
3MRI 2010-04-29T00:00:00+0000 2.1 Crystal Structure of MHC class I HLA-A2 molecule complexed with HCV NS3-1073-1081 nonapeptide G4M-V5W variant
3MRH 2010-04-29T00:00:00+0000 2.4 Crystal Structure of MHC class I HLA-A2 molecule complexed with HCV NS3-1073-1081 nonapeptide N3S variant
3MRL 2010-04-29T00:00:00+0000 2.41 Crystal Structure of MHC class I HLA-A2 molecule complexed with HCV NS3-1073-1081 nonapeptide C6V variant
3MRJ 2010-04-29T00:00:00+0000 1.87 Crystal Structure of MHC class I HLA-A2 molecule complexed with HCV NS3-1073-1081 nonapeptide V5M variant
3MRG 2010-04-29T00:00:00+0000 1.3 Crystal Structure of MHC class I HLA-A2 molecule complexed with HCV NS3-1073-1081 nonapeptide
1RTL 2003-12-10T00:00:00+0000 2.75 CRYSTAL STRUCTURE OF HCV NS3 PROTEASE DOMAIN: NS4A PEPTIDE COMPLEX WITH COVALENTLY BOUND PYRROLIDINE-5,5-TRANSLACTAM INHIBITOR
3SU4 2011-07-11T00:00:00+0000 2.25 Crystal structure of NS3/4A protease variant R155K in complex with vaniprevir

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
96.9 hepatitis C virus E2 glycoprotein P27954 POLG_HCVE1
90.3 hepatitis C virus E2 glycoprotein P27955 POLG_HCVH7
91.3 hepatitis C virus E2 glycoprotein P27957 POLG_HCVTH
92.2 hepatitis C virus E2 glycoprotein P27956 POLG_HCVH8
93.4 hepatitis C virus E2 glycoprotein Q5EG65 POLG_HCVGL
95.2 hepatitis C virus E2 glycoprotein Q03463 POLG_HCVJ1
95.9 hepatitis C virus E2 glycoprotein P26664 POLG_HCV1
100.0 hepatitis C virus E2 glycoprotein P27958 POLG_HCVH