An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein
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.
- Authors:
-
[1];
[2];
[1]
- California Institute of Technology (CalTech), Pasadena, CA (United States). Division of Biology and Biological Engineering
- California Institute of Technology (CalTech), Pasadena, CA (United States). Division of Biology and Biological Engineering; Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine. Dept. of Medicine
- Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine. Dept. of Medicine
- Publication Date:
- Research Org.:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
- OSTI Identifier:
- 1628916
- Grant/Contract Number:
- AC02-76SF00515
- Resource Type:
- Accepted Manuscript
- Journal Name:
- eLife
- Additional Journal Information:
- Journal Volume: 9; Journal ID: ISSN 2050-084X
- Publisher:
- eLife Sciences Publications, Ltd.
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Life Sciences & Biomedicine - Other Topics
Citation Formats
Flyak, Andrew I., Ruiz, Stormy E., Salas, Jordan, Rho, Semi, Bailey, Justin R., and Bjorkman, Pamela J. An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein. United States: N. p., 2020.
Web. doi:10.7554/elife.53169.
Flyak, Andrew I., Ruiz, Stormy E., Salas, Jordan, Rho, Semi, Bailey, Justin R., & Bjorkman, Pamela J. An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein. United States. https://doi.org/10.7554/elife.53169
Flyak, Andrew I., Ruiz, Stormy E., Salas, Jordan, Rho, Semi, Bailey, Justin R., and Bjorkman, Pamela J. Tue .
"An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein". United States. https://doi.org/10.7554/elife.53169. https://www.osti.gov/servlets/purl/1628916.
@article{osti_1628916,
title = {An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein},
author = {Flyak, Andrew I. and Ruiz, Stormy E. and Salas, Jordan and Rho, Semi and Bailey, Justin R. and Bjorkman, Pamela J.},
abstractNote = {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.},
doi = {10.7554/elife.53169},
journal = {eLife},
number = ,
volume = 9,
place = {United States},
year = {Tue Mar 03 00:00:00 EST 2020},
month = {Tue Mar 03 00:00:00 EST 2020}
}
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