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Neutralizing monoclonal antibodies against hepatitis C virus E2 protein bind discontinuous epitopes and inhibit infection at a postattachment step

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. CO-HEP; Copenhagen Hepatitis C Program

    Projekt: Typer af projekter

  1. Replicons of a rodent hepatitis C model virus permit selection of highly permissive cells

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. IDENTIFICATION OF PIPERAZINYLBENZENESULFONAMIDES AS NEW INHIBITORS OF CLAUDIN-1 TRAFFICKING AND HEPATITIS C VIRUS ENTRY

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Development of a downstream process for the production of an inactivated whole hepatitis C virus vaccine

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Global and local envelope protein dynamics of hepatitis C virus determine broad antibody sensitivity

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. An alternate conformation of HCV E2 neutralizing face as an additional vaccine target

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Michelle C Sabo
  • Vincent C Luca
  • Jannick Prentoe
  • Sharon E Hopcraft
  • Keril J Blight
  • Minkyung Yi
  • Stanley M Lemon
  • Jonathan K Ball
  • Jens Bukh
  • Matthew J Evans
  • Daved H Fremont
  • Michael S Diamond
Vis graf over relationer
The E2 glycoprotein of hepatitis C virus (HCV) mediates viral attachment and entry into target hepatocytes and elicits neutralizing antibodies in infected patients. To characterize the structural and functional basis of HCV neutralization, we generated a novel panel of 78 monoclonal antibodies (MAbs) against E2 proteins from genotype 1a and 2a HCV strains. Using high-throughput focus-forming reduction or luciferase-based neutralization assays with chimeric infectious HCV containing structural proteins from both genotypes, we defined eight MAbs that significantly inhibited infection of the homologous HCV strain in cell culture. Two of these bound E2 proteins from strains representative of HCV genotypes 1 to 6, and one of these MAbs, H77.39, neutralized infection of strains from five of these genotypes. The three most potent neutralizing MAbs in our panel, H77.16, H77.39, and J6.36, inhibited infection at an early postattachment step. Receptor binding studies demonstrated that H77.39 inhibited binding of soluble E2 protein to both CD81 and SR-B1, J6.36 blocked attachment to SR-B1 and modestly reduced binding to CD81, and H77.16 blocked attachment to SR-B1 only. Using yeast surface display, we localized epitopes for the neutralizing MAbs on the E2 protein. Two of the strongly inhibitory MAbs, H77.16 and J6.36, showed markedly reduced binding when amino acids within hypervariable region 1 (HVR1) and at sites ∼100 to 200 residues away were changed, suggesting binding to a discontinuous epitope. Collectively, these studies help to define the structural and functional complexity of antibodies against HCV E2 protein with neutralizing potential.
OriginalsprogEngelsk
TidsskriftJournal of Virology
Vol/bind85
Udgave nummer14
Sider (fra-til)7005-19
Antal sider15
ISSN0022-538X
DOI
StatusUdgivet - jul. 2011

ID: 33107411