Escape of Hepatitis C Virus from Epitope I Neutralization Increases Sensitivity of Other Neutralization Epitopes

Journal of Virology
Jun GuHeidi E Drummer

Abstract

The hepatitis C virus (HCV) E2 glycoprotein is a major target of the neutralizing antibody (nAb) response, with multiple type-specific and broadly neutralizing antibody (bnAb) epitopes identified. The 412-to-423 region can generate bnAbs that block interaction with the cell surface receptor CD81, with activity toward multiple HCV genotypes. In this study, we reveal the structure of rodent monoclonal antibody 24 (MAb24) with an extensive contact area toward a peptide spanning the 412-to-423 region. The crystal structure of the MAb24-peptide 412-to-423 complex reveals the paratope bound to a peptide hairpin highly similar to that observed with human MAb HCV1 and rodent MAb AP33, but with a different angle of approach. In viral outgrowth experiments, we demonstrated three distinct genotype 2a viral populations that acquired resistance to MAb24 via N415D, N417S, and N415D/H386R mutations. Importantly, the MAb24-resistant viruses exhibited significant increases in sensitivity to the majority of bnAbs directed to epitopes within the 412-to-423 region and in additional antigenic determinants located within E2 and the E1E2 complex. This study suggests that modification of N415 causes a global change in glycoprotein structure that incre...Continue Reading

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Citations

Feb 23, 2020·Vaccines·Joshua D DuncanJonathan K Ball
Jun 13, 2018·Frontiers in Immunology·Johnathan D Guest, Brian G Pierce
Jun 29, 2018·Frontiers in Immunology·Netanel TzarumMansun Law
Sep 20, 2020·International Journal of Molecular Sciences·Luisa J Ströh, Thomas Krey
Jul 4, 2018·Frontiers in Immunology·Luisa J StröhThomas Krey
Oct 11, 2020·The Journal of Infectious Diseases·Ahmed Atef Mesalam
Jan 10, 2021·NPJ Vaccines·Vanessa M CowtonArvind H Patel
Apr 4, 2021·Vaccines·Rodrigo Velázquez-MoctezumaJannick Prentoe
May 6, 2021·Viruses·Felicia SchlotthauerHeidi E Drummer
Jun 3, 2021·Viruses·Itai YechezkelNetanel Tzarum
Jul 31, 2021·Current Opinion in Virology·Nicole FrumentoJustin R Bailey
Aug 18, 2021·Current Opinion in Virology·Elias H AugestadJannick Prentoe

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Methods Mentioned

BETA
glycosylation
transfection
electron microscopy
reverse transcription-PCR
PCR

Software Mentioned

Coot
Prism
Phaser
CCP4
GlyProt
PyMOL PyMOL Molecular Graphics System
Phenix suite
POINTLESS
Proteins , Interfaces , Structures , and Assemblies
BUSTER

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