title: A Hepatitis C Virus Envelope Polymorphism Confers Resistance to Neutralization by Polyclonal Sera and Broadly Neutralizing Monoclonal Antibodies.
abstract: Hepatitis C virus (HCV) infection is a global health problem, with millions of chronically infected individuals at risk for cirrhosis and hepatocellular carcinoma. HCV vaccine development is vital in the effort toward disease control and eradication, an undertaking aided by an increased understanding of the mechanisms of resistance to broadly neutralizing antibodies (bNAbs). In this study, we identified HCV codons that vary deep in a phylogenetic tree of HCV sequences and showed that a polymorphism at one of these positions renders Bole1a, a computationally derived, ancestral genotype 1a HCV strain, resistant to neutralization by both polyclonal-HCV-infected plasma and multiple broadly neutralizing monoclonal antibodies with unique binding epitopes. This bNAb resistance mutation reduces replicative fitness, which may explain the persistence of both neutralization-sensitive and neutralization-resistant variants in circulating viral strains. This work identifies an important determinant of bNAb resistance in an ancestral, representative HCV genome, which may inform HCV vaccine development.
  
  
  OBJECTIVE
  Worldwide, more than 170 million people are infected with hepatitis C virus (HCV), the leading cause of hepatocellular carcinoma and liver transplantation in the United States. Despite recent significant advances in HCV treatment, a vaccine is needed. Control of the HCV pandemic with drug treatment alone is likely to fail due to limited access to treatment, reinfections in high-risk individuals, and the potential for resistance to direct-acting antivirals (DAAs). Broadly neutralizing antibodies (bNAbs) block infection by diverse HCV variants and therefore serve as a useful guide for vaccine development, but our understanding of resistance to bNAbs is incomplete. In this report, we identify a viral polymorphism conferring resistance to neutralization by both polyclonal plasma and broadly neutralizing monoclonal antibodies, which may inform HCV vaccine development.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Wasilewski
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ramy
authors.initials: R
authors.lastname: El-Diwany
authors.affiliation: Carey Business School, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Munshaw
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Snider
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jillian K
authors.initials: JK
authors.lastname: Brady
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: William O
authors.initials: WO
authors.lastname: Osburn
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Ray
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA jbailey7@jhmi.edu.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Bailey
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D018937:Hepatitis C Antibodies / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic; D014779:Virus Replication
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015686:Gene Products, env; D018937:Hepatitis C Antibodies; D050505:Mutant Proteins
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