Escape of hepatitis C virus from epitope I neutralization increases sensitivity of other neutralization epitopes

Jun Gu, Joshua Hardy, Irene Boo, Patricia Vietheer, Kathleen McCaffrey, Yousef Alhammad, Abha Chopra, Silvana Gaudieri, Pantelis Poumbourios, Fasséli Coulibaly, Heidi E. Drummer

Research output: Contribution to journalArticleResearchpeer-review

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 increases its vulnerability to neutralization by other antibodies. This finding suggests that in the context of an antibody response to viral infection, acquisition of escape mutations in the 412-to-423 region renders the virus more susceptible to neutralization by other specificities of nAbs, effectively reducing the immunological fitness of the virus. A vaccine for HCV that generates polyspecific humoral immunity with specificity for the 412-to-423 region and at least one other region of E2 is desirable.

Original languageEnglish
Article numbere02066-17
Number of pages18
JournalJournal of Virology
Volume92
Issue number9
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • Glycoproteins
  • Hepatitis C virus
  • Neutralizing antibodies
  • Vaccines

Cite this

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title = "Escape of hepatitis C virus from epitope I neutralization increases sensitivity of other neutralization epitopes",
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 increases its vulnerability to neutralization by other antibodies. This finding suggests that in the context of an antibody response to viral infection, acquisition of escape mutations in the 412-to-423 region renders the virus more susceptible to neutralization by other specificities of nAbs, effectively reducing the immunological fitness of the virus. A vaccine for HCV that generates polyspecific humoral immunity with specificity for the 412-to-423 region and at least one other region of E2 is desirable.",
keywords = "Glycoproteins, Hepatitis C virus, Neutralizing antibodies, Vaccines",
author = "Jun Gu and Joshua Hardy and Irene Boo and Patricia Vietheer and Kathleen McCaffrey and Yousef Alhammad and Abha Chopra and Silvana Gaudieri and Pantelis Poumbourios and Fass{\'e}li Coulibaly and Drummer, {Heidi E.}",
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Escape of hepatitis C virus from epitope I neutralization increases sensitivity of other neutralization epitopes. / Gu, Jun; Hardy, Joshua; Boo, Irene; Vietheer, Patricia; McCaffrey, Kathleen; Alhammad, Yousef; Chopra, Abha; Gaudieri, Silvana; Poumbourios, Pantelis; Coulibaly, Fasséli; Drummer, Heidi E.

In: Journal of Virology, Vol. 92, No. 9, e02066-17, 01.05.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Escape of hepatitis C virus from epitope I neutralization increases sensitivity of other neutralization epitopes

AU - Gu, Jun

AU - Hardy, Joshua

AU - Boo, Irene

AU - Vietheer, Patricia

AU - McCaffrey, Kathleen

AU - Alhammad, Yousef

AU - Chopra, Abha

AU - Gaudieri, Silvana

AU - Poumbourios, Pantelis

AU - Coulibaly, Fasséli

AU - Drummer, Heidi E.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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 increases its vulnerability to neutralization by other antibodies. This finding suggests that in the context of an antibody response to viral infection, acquisition of escape mutations in the 412-to-423 region renders the virus more susceptible to neutralization by other specificities of nAbs, effectively reducing the immunological fitness of the virus. A vaccine for HCV that generates polyspecific humoral immunity with specificity for the 412-to-423 region and at least one other region of E2 is desirable.

AB - 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 increases its vulnerability to neutralization by other antibodies. This finding suggests that in the context of an antibody response to viral infection, acquisition of escape mutations in the 412-to-423 region renders the virus more susceptible to neutralization by other specificities of nAbs, effectively reducing the immunological fitness of the virus. A vaccine for HCV that generates polyspecific humoral immunity with specificity for the 412-to-423 region and at least one other region of E2 is desirable.

KW - Glycoproteins

KW - Hepatitis C virus

KW - Neutralizing antibodies

KW - Vaccines

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DO - 10.1128/JVI.02066-17

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