Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus 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 t...

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Autores principales:	Ieva Vasiliauskaite, Ania Owsianka, Patrick England, Abdul Ghafoor Khan, Sarah Cole, Dorothea Bankwitz, Steven K. H. Foung, Thomas Pietschmann, Joseph Marcotrigiano, Felix A. Rey, Arvind H. Patel, Thomas Krey
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	CD81 binding site hepatitis C virus Ig-like domain conformational flexibility glycoprotein E2 monoclonal antibodies Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a3bea6c8045c419198f363ad02f506f7
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spelling	oai:doaj.org-article:a3bea6c8045c419198f363ad02f506f72021-11-15T15:51:28ZConformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E210.1128/mBio.00382-172150-7511https://doaj.org/article/a3bea6c8045c419198f363ad02f506f72017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00382-17https://doaj.org/toc/2150-7511ABSTRACT 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.Ieva VasiliauskaiteAnia OwsiankaPatrick EnglandAbdul Ghafoor KhanSarah ColeDorothea BankwitzSteven K. H. FoungThomas PietschmannJoseph MarcotrigianoFelix A. ReyArvind H. PatelThomas KreyAmerican Society for MicrobiologyarticleCD81 binding sitehepatitis C virusIg-like domainconformational flexibilityglycoprotein E2monoclonal antibodiesMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	CD81 binding site hepatitis C virus Ig-like domain conformational flexibility glycoprotein E2 monoclonal antibodies Microbiology QR1-502
spellingShingle	CD81 binding site hepatitis C virus Ig-like domain conformational flexibility glycoprotein E2 monoclonal antibodies Microbiology QR1-502 Ieva Vasiliauskaite Ania Owsianka Patrick England Abdul Ghafoor Khan Sarah Cole Dorothea Bankwitz Steven K. H. Foung Thomas Pietschmann Joseph Marcotrigiano Felix A. Rey Arvind H. Patel Thomas Krey Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2
description	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.
format	article
author	Ieva Vasiliauskaite Ania Owsianka Patrick England Abdul Ghafoor Khan Sarah Cole Dorothea Bankwitz Steven K. H. Foung Thomas Pietschmann Joseph Marcotrigiano Felix A. Rey Arvind H. Patel Thomas Krey
author_facet	Ieva Vasiliauskaite Ania Owsianka Patrick England Abdul Ghafoor Khan Sarah Cole Dorothea Bankwitz Steven K. H. Foung Thomas Pietschmann Joseph Marcotrigiano Felix A. Rey Arvind H. Patel Thomas Krey
author_sort	Ieva Vasiliauskaite
title	Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2
title_short	Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2
title_full	Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2
title_fullStr	Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2
title_full_unstemmed	Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2
title_sort	conformational flexibility in the immunoglobulin-like domain of the hepatitis c virus glycoprotein e2
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/a3bea6c8045c419198f363ad02f506f7
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Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2

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