Journal article
Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1
PLoS pathogens, Vol.13(2), p.e1006235
02/01/2017
DOI: 10.1371/journal.ppat.1006235
PMCID: PMC5342271
PMID: 28235087
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.
Details
- Title: Subtitle
- Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1
- Creators
- Ramy El-Diwany - Johns Hopkins University School of MedicineValerie J Cohen - Johns Hopkins MedicineMadeleine C Mankowski - Johns Hopkins MedicineLisa N Wasilewski - Johns Hopkins UniversityJillian K Brady - Johns Hopkins MedicineAnna E Snider - Johns Hopkins UniversityWilliam O Osburn - Johns Hopkins UniversityBen Murrell - University of California San DiegoStuart C Ray - Johns Hopkins UniversityJustin R Bailey - Johns Hopkins University
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.13(2), p.e1006235
- DOI
- 10.1371/journal.ppat.1006235
- PMID
- 28235087
- PMCID
- PMC5342271
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7374
- eISSN
- 1553-7374
- Grant note
- U19 AI088791 / NIAID NIH HHS P30 AI094189 / NIAID NIH HHS T32 AI007247 / NIAID NIH HHS K08 AI102761 / NIAID NIH HHS T32 GM007309 / NIGMS NIH HHS T32 GM008752 / NIGMS NIH HHS
- Language
- English
- Date published
- 02/01/2017
- Academic Unit
- Surgery
- Record Identifier
- 9984966855802771
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