title: Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1.
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.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Ramy
authors.initials: R
authors.lastname: El-Diwany
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Valerie J
authors.identifier: 0000-0003-2317-9990
authors.initials: VJ
authors.lastname: Cohen
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Madeleine C
authors.initials: MC
authors.lastname: Mankowski
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Wasilewski
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Jillian K
authors.initials: JK
authors.lastname: Brady
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Snider
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: William O
authors.initials: WO
authors.lastname: Osburn
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Ben
authors.initials: B
authors.lastname: Murrell
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Ray
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Justin R
authors.identifier: 0000-0001-5704-3130
authors.initials: JR
authors.lastname: Bailey
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006526:Hepatitis C / Q000276:immunology; D018937:Hepatitis C Antibodies / Q000276:immunology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D016297:Mutagenesis, Site-Directed; D009500:Neutralization Tests; D010802:Phylogeny; D011110:Polymorphism, Genetic; D051122:Scavenger Receptors, Class B / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; C087035:E1 protein, Hepatitis C virus; D018937:Hepatitis C Antibodies; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus