scholarly journals The core domain of hepatitis C virus glycoprotein E2 generates potent cross-neutralizing antibodies in guinea pigs

Hepatology ◽  
2017 ◽  
Vol 65 (4) ◽  
pp. 1117-1131 ◽  
Author(s):  
Patricia T. Vietheer ◽  
Irene Boo ◽  
Jun Gu ◽  
Kathleen McCaffrey ◽  
Stirling Edwards ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Guinea Pigs ◽  
Neutralizing Antibodies ◽  
Core Domain ◽  
Virus Glycoprotein ◽  
The Core ◽  
Glycoprotein E2

scholarly journals Interplay between Basic Residues of Hepatitis C Virus Glycoprotein E2 with Viral Receptors, Neutralizing Antibodies and Lipoproteins

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e52651 ◽  
Author(s):  
George Koutsoudakis ◽  
Jakub Dragun ◽  
Sofia Pérez-del-Pulgar ◽  
Mairene Coto-Llerena ◽  
Laura Mensa ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Virus Glycoprotein ◽  
Glycoprotein E2 ◽  
Viral Receptors

849 INTERPLAY BETWEEN BASIC RESIDUES OF HEPATITIS C VIRUS GLYCOPROTEIN E2 WITH LIPOPROTEINS, VIRAL RECEPTORS AND NEUTRALIZING ANTIBODIES

2012 ◽  
Vol 56 ◽  
pp. S331
Author(s):  
G. Koutsoudakis ◽  
J. Dragun ◽  
S. Perez del Pulgar ◽  
M. Coto-Llerena ◽  
L. Mensa ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Virus Glycoprotein ◽  
Glycoprotein E2 ◽  
Viral Receptors

scholarly journals Expression and Characterization of a Minimal Hepatitis C Virus Glycoprotein E2 Core Domain That Retains CD81 Binding

2007 ◽  
Vol 81 (17) ◽  
pp. 9584-9590 ◽  
Author(s):  
Kathleen McCaffrey ◽  
Irene Boo ◽  
Pantelis Poumbourios ◽  
Heidi E. Drummer
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Variable Region ◽  
Sequence Comparisons ◽  
Variable Regions ◽  
Core Domain ◽  
Virus Glycoprotein ◽  
Glycoprotein E2 ◽  
Cd81 Binding

ABSTRACT The hepatitis C virus glycoprotein E2 receptor-binding domain is encompassed by amino acids 384 to 661 (E2661) and contains two hypervariable sequences, HVR1 and HVR2. E2 sequence comparisons revealed a third variable region, located between residues 570 and 580, that varies widely between genotypes, designated here as igVR, the intergenotypic variable region. A secreted E2661 glycoprotein with simultaneous deletions of the three variable sequences retained its ability to bind CD81 and conformation-dependent monoclonal antibodies (MAbs) and displayed enhanced binding to a neutralizing MAb directed to E2 immunogenic domain B. Our data provide insights into the E2 structure by suggesting that the three variable regions reside outside a conserved E2 core.

scholarly journals Virus-Like Particles Containing the E2 Core Domain of Hepatitis C Virus Generate Broadly Neutralizing Antibodies in Guinea Pigs.

2022 ◽  
Author(s):  
Joey McGregor ◽  
Joshua M. Hardy ◽  
Chan-Sien Lay ◽  
Irene Boo ◽  
Michael Piontek ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Guinea Pigs ◽  
Neutralizing Antibodies ◽  
Large Scale ◽  
Broadly Neutralizing Antibodies ◽  
Virus Like Particles ◽  
Duck Hepatitis ◽  
B Virus ◽  
Glycoprotein E2

A vaccine to prevent hepatitis C virus (HCV) infection is urgently needed for use alongside direct acting antiviral drugs to achieve elimination targets. We have previously shown that a soluble recombinant form of the glycoprotein E2 ectodomain (residues 384-661), that lacks three variable regions (Δ123) is able to elicit a higher titer of broadly neutralizing antibodies (bnAbs) in comparison to the parental form (receptor-binding domain; RBD). In this study, we engineered a viral nanoparticle that displays HCV glycoprotein E2 on a duck hepatitis B virus (DHBV) small surface antigen (S) scaffold. Four variants of E2-S virus-like particles (VLPs) were constructed: Δ123-S and RBD-S, and Δ123A7-S and RBDA7-S in which 7 cysteines were replaced with alanines. While all four E2-S VLPs display E2 as a surface antigen, the Δ123A7-S and RBDA7-S VLPs were the most efficiently secreted from transfected mammalian cells, and displayed epitopes recognized by cross-genotype broadly neutralizing monoclonal antibodies (bnmAbs). Both Δ123A7-S and RBDA7-S VLPs were immunogenic in guinea pigs, generating high titers of antibodies reactive to native E2 and able to prevent the interaction between E2 and the cellular receptor CD81. Four out of eight animals immunized with Δ123A7-S elicited neutralizing antibodies (nAbs), with three of those animals generating bnAbs against 7 genotypes. Immune serum generated by animals with nAbs mapped to major neutralization epitopes located at residues 412-420 (epitope I) and antigenic region 3. VLPs that display E2 glycoproteins represent a promising vaccine platform for HCV and could be adapted to large-scale manufacturing in yeast systems. IMPORTANCE There is currently no vaccine to prevent hepatitis C virus infection, which affects more than 71 million people globally and is a leading cause of progressive liver disease including cirrhosis and cancer. Broadly neutralizing antibodies that recognise the E2 envelope glycoprotein can protect against heterologous viral infection and correlate with viral clearance in humans. However, broadly neutralizing antibodies are difficult to generate due to conformational flexibility of the E2 protein and epitope occlusion. Here we show that a VLP vaccine using the duck hepatitis B virus S antigen fused to HCV glycoprotein E2 assembles into virus like particles that display epitopes recognised by broadly neutralizing antibodies and elicit such antibodies in guinea pigs. This platform represents a novel HCV vaccine candidate amenable to large-scale manufacture at low cost.

scholarly journals Hepatitis C Virus Glycoprotein E2 Binding to CD81: The Role of E1E2 Cleavage and Protein Glycosylation in Bioactivity

Virology ◽  
2000 ◽  
Vol 273 (1) ◽  
pp. 60-66 ◽  
Author(s):  
Christine Chan-Fook ◽  
Wen-Rong Jiang ◽  
Berwyn E. Clarke ◽  
Nicole Zitzmann ◽  
Catherine Maidens ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protein Glycosylation ◽  
Virus Glycoprotein ◽  
Glycoprotein E2

scholarly journals Role of Conserved Cysteine Residues in Hepatitis C Virus Glycoprotein E2 Folding and Function

2012 ◽  
Vol 86 (7) ◽  
pp. 3961-3974 ◽  
Author(s):  
K. McCaffrey ◽  
I. Boo ◽  
K. Tewierek ◽  
M. L. Edmunds ◽  
P. Poumbourios ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cysteine Residues ◽  
Virus Glycoprotein ◽  
Glycoprotein E2 ◽  
And Function

scholarly journals Structural Flexibility of a Conserved Antigenic Region in Hepatitis C Virus Glycoprotein E2 Recognized by Broadly Neutralizing Antibodies

2014 ◽  
Vol 89 (4) ◽  
pp. 2170-2181 ◽  
Author(s):  
Annalisa Meola ◽  
Alexander W. Tarr ◽  
Patrick England ◽  
Luke W. Meredith ◽  
C. Patrick McClure ◽  
...  
Keyword(s):  
Amino Acids ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Antigenic Site ◽  
Conformational Flexibility ◽  
Structural Flexibility ◽  
Viral Spread ◽  
Antigenic Region ◽  
Glycoprotein E2

ABSTRACTNeutralizing antibodies (NAbs) targeting glycoprotein E2 are important for the control of hepatitis C virus (HCV) infection. One conserved antigenic site (amino acids 412 to 423) is disordered in the reported E2 structure, but a synthetic peptide mimicking this site forms a β-hairpin in complex with three independent NAbs. Our structure of the same peptide in complex with NAb 3/11 demonstrates a strikingly different extended conformation. We also show that residues 412 to 423 are essential for virus entry but not for E2 folding. Together with the neutralizing capacity of the 3/11 Fab fragment, this indicates an unexpected structural flexibility within this epitope. NAbs 3/11 and AP33 (recognizing the extended and β-hairpin conformations, respectively) display similar neutralizing activities despite converse binding kinetics. Our results suggest that HCV utilizes conformational flexibility as an immune evasion strategy, contributing to the limited immunogenicity of this epitope in patients, similar to the conformational flexibility described for other enveloped and nonenveloped viruses.IMPORTANCEApproximately 180 million people worldwide are infected with hepatitis C virus (HCV), and neutralizing antibodies play an important role in controlling the replication of this major human pathogen. We show here that one of the most conserved antigenic sites within the major glycoprotein E2 (amino acids 412 to 423), which is disordered in the recently reported crystal structure of an E2 core fragment, can adopt different conformations in the context of the infectious virus particle. Recombinant Fab fragments recognizing different conformations of this antigenic site have similar neutralization activities in spite of converse kinetic binding parameters. Of note, an antibody response targeting this antigenic region is less frequent than those targeting other more immunogenic regions in E2. Our results suggest that the observed conformational flexibility in this conserved antigenic region contributes to the evasion of the humoral host immune response, facilitating chronicity and the viral spread of HCV within an infected individual.

scholarly journals Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2

mBio ◽  
2017 ◽  
Vol 8 (3) ◽  
Author(s):  
Ieva Vasiliauskaite ◽  
Ania Owsianka ◽  
Patrick England ◽  
Abdul Ghafoor Khan ◽  
Sarah Cole ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Binding Site ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Asymptomatic Infection ◽  
Effective Vaccine ◽  
Viral Glycoprotein ◽  
Direct Acting Antiviral ◽  
Glycoprotein E2

ABSTRACT The hepatitis C virus (HCV) glycoprotein E2 is the major target of neutralizing antibodies and is therefore highly relevant for vaccine design. Its structure features a central immunoglobulin (Ig)-like β-sandwich that contributes to the binding site for the cellular receptor CD81. We show that a synthetic peptide corresponding to a β-strand of this Ig-like domain forms an α-helix in complex with the anti-E2 antibody DAO5, demonstrating an inside-out flip of hydrophobic residues and a secondary structure change in the composite CD81 binding site. A detailed interaction analysis of DAO5 and cross-competing neutralizing antibodies with soluble E2 revealed that the Ig-like domain is trapped by different antibodies in at least two distinct conformations. DAO5 specifically captures retrovirus particles bearing HCV glycoproteins (HCVpp) and infectious cell culture-derived HCV particles (HCVcc). Infection of cells by DAO5-captured HCVpp can be blocked by a cross-competing neutralizing antibody, indicating that a single virus particle simultaneously displays E2 molecules in more than one conformation on its surface. Such conformational plasticity of the HCV E2 receptor binding site has important implications for immunogen design. IMPORTANCE Recent advances in the treatment of hepatitis C virus (HCV) infection with direct-acting antiviral drugs have enabled the control of this major human pathogen. However, due to their high costs and limited accessibility in combination with the lack of awareness of the mostly asymptomatic infection, there is an unchanged urgent need for an effective vaccine. The viral glycoprotein E2 contains regions that are crucial for virus entry into the host cell, and antibodies that bind to these regions can neutralize infection. One of the major targets of neutralizing antibodies is the central immunoglobulin (Ig)-like domain within E2. We show here that this Ig-like domain is conformationally flexible at the surface of infectious HCV particles and pseudoparticles. Our study provides novel insights into the interactions of HCV E2 with the humoral immune system that should aid future vaccine development. IMPORTANCE Recent advances in the treatment of hepatitis C virus (HCV) infection with direct-acting antiviral drugs have enabled the control of this major human pathogen. However, due to their high costs and limited accessibility in combination with the lack of awareness of the mostly asymptomatic infection, there is an unchanged urgent need for an effective vaccine. The viral glycoprotein E2 contains regions that are crucial for virus entry into the host cell, and antibodies that bind to these regions can neutralize infection. One of the major targets of neutralizing antibodies is the central immunoglobulin (Ig)-like domain within E2. We show here that this Ig-like domain is conformationally flexible at the surface of infectious HCV particles and pseudoparticles. Our study provides novel insights into the interactions of HCV E2 with the humoral immune system that should aid future vaccine development.

Sign in / Sign up

Export Citation Format

Share Document