An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein

Abstract
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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

1. Flyak AI
2. Bjorkman PJ
(2020) Crystal structure of broadly neutralizing antibody AR3X in complex with Hepatitis C virus envelope glycoprotein E2 ectodomain
Protein Data Bank, 6URH.

https://www.rcsb.org/structure/6URH

Article and author information

Author details

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..
Stormy E Ruiz

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-0892-9626
Jordan Salas

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States

Competing interests
No competing interests declared.
Semi Rho

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

Competing interests
No competing interests declared.
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..
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.

"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.

Copyright

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.