1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
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An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein

  1. Andrew I Flyak
  2. Stormy E Ruiz
  3. Jordan Salas
  4. Semi Rho
  5. Justin R Bailey
  6. Pamela J Bjorkman  Is a corresponding author
  1. California Institute of Technology, United States
  2. Johns Hopkins University School of Medicine, United States
Research Article
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Cite this article as: eLife 2020;9:e53169 doi: 10.7554/eLife.53169

Abstract

A vaccine protective against diverse HCV variants is needed to control the HCV epidemic. Structures of E2 complexes with front layer-specific broadly neutralizing antibodies (bNAbs) isolated from HCV-infected individuals, revealed a disulfide bond-containing CDRH3 that adopts straight (individuals who clear infection) or bent (individuals with chronic infection) conformation. To investigate whether a straight versus bent disulfide bond-containing CDRH3 is specific to particular HCV-infected individuals, we solved a crystal structure of the HCV E2 ectodomain in complex with AR3X, a bNAb with an unusually long CDRH2 that was isolated from the chronically-infected individual from whom the bent CDRH3 bNAbs were derived. The structure revealed that AR3X utilizes both its ultralong CDRH2 and a disulfide motif-containing straight CDRH3 to recognize the E2 front layer. These results demonstrate that both the straight and bent CDRH3 classes of HCV bNAb can be elicited in a single individual, revealing a structural plasticity of VH1-69-derived bNAbs.

Data availability

Diffraction data have been deposited in PDB under the accession code 6URH.

The following data sets were generated

Article and author information

Author details

  1. Andrew I Flyak

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    Andrew I Flyak, A.I.F. and J.R.B. are inventors of International Patent Application, Serial no. PCT/US2019/029315, pertaining to some of the antibodies presented in this article..
  2. Stormy E Ruiz

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0892-9626
  3. Jordan Salas

    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  4. Semi Rho

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  5. Justin R Bailey

    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    Justin R Bailey, A.I.F. and J.R.B. are inventors of International Patent Application, Serial no. PCT/US2019/029315, pertaining to some of the antibodies presented in this article..
  6. Pamela J Bjorkman

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    bjorkman@caltech.edu
    Competing interests
    Pamela J Bjorkman, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2277-3990

Funding

National Institutes of Health (R01 AI127469)

  • Justin R Bailey
  • Pamela J Bjorkman

Cancer Research Institute (Irvington Postdoctoral Fellowship)

  • Andrew I Flyak

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Wenhui Li, National Institute of Biological Sciences, China

Publication history

  1. Received: October 30, 2019
  2. Accepted: March 2, 2020
  3. Accepted Manuscript published: March 3, 2020 (version 1)
  4. Version of Record published: March 10, 2020 (version 2)

Copyright

© 2020, Flyak et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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