Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1

Ramy El-Diwany, Valerie J. Cohen, Madeleine C. Mankowski, Lisa N. Wasilewski, Jillian K. Brady, Anna E. Snider, William O. Osburn, Ben Murrell, Stuart C. Ray, Justin R. Bailey

Research output: Contribution to journalArticle

Abstract

Broadly-neutralizing monoclonal antibodies (bNAbs) may guide vaccine development for highly variable viruses including hepatitis C virus (HCV), since they target conserved viral epitopes that could serve as vaccine antigens. However, HCV resistance to bNAbs could reduce the efficacy of a vaccine. HC33.4 and AR4A are two of the most potent anti-HCV human bNAbs characterized to date, binding to highly conserved epitopes near the amino- and carboxy-terminus of HCV envelope (E2) protein, respectively. Given their distinct epitopes, it was surprising that these bNAbs showed similar neutralization profiles across a panel of natural HCV isolates, suggesting that some viral polymorphisms may confer resistance to both bNAbs. To investigate this resistance, we developed a large, diverse panel of natural HCV envelope variants and a novel computational method to identify bNAb resistance polymorphisms in envelope proteins (E1 and E2). By measuring neutralization of a panel of HCV pseudoparticles by 10 μg/mL of each bNAb, we identified E1E2 variants with resistance to one or both bNAbs, despite 100% conservation of the AR4A binding epitope across the panel. We discovered polymorphisms outside of either binding epitope that modulate resistance to both bNAbs by altering E2 binding to the HCV co-receptor, scavenger receptor B1 (SR-B1). This study is focused on a mode of neutralization escape not addressed by conventional analysis of epitope conservation, highlighting the contribution of extra-epitopic polymorphisms to bNAb resistance and presenting a novel mechanism by which HCV might persist even in the face of an antibody response targeting multiple conserved epitopes.

Original languageEnglish (US)
Article numbere1006235
JournalPLoS Pathogens
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2017

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Scavenger Receptors
Neutralizing Antibodies
Hepacivirus
Epitopes
Monoclonal Antibodies
Vaccines
Viral Envelope Proteins
Virus Receptors
Antibody Formation
Viruses
Antigens
Proteins

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1. / El-Diwany, Ramy; Cohen, Valerie J.; Mankowski, Madeleine C.; Wasilewski, Lisa N.; Brady, Jillian K.; Snider, Anna E.; Osburn, William O.; Murrell, Ben; Ray, Stuart C.; Bailey, Justin R.

In: PLoS Pathogens, Vol. 13, No. 2, e1006235, 01.02.2017.

Research output: Contribution to journalArticle

El-Diwany R, Cohen VJ, Mankowski MC, Wasilewski LN, Brady JK, Snider AE et al. Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1. PLoS Pathogens. 2017 Feb 1;13(2). e1006235. Available from, DOI: 10.1371/journal.ppat.1006235

El-Diwany, Ramy; Cohen, Valerie J.; Mankowski, Madeleine C.; Wasilewski, Lisa N.; Brady, Jillian K.; Snider, Anna E.; Osburn, William O.; Murrell, Ben; Ray, Stuart C.; Bailey, Justin R. / Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1.

In: PLoS Pathogens, Vol. 13, No. 2, e1006235, 01.02.2017.

Research output: Contribution to journalArticle

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