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

Flyak, Andrew I.; Ruiz, Stormy E.; Salas, Jordan; Rho, Semi; Bailey, Justin R.; Bjorkman, Pamela J.

doi:10.7554/elife.53169

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

Journal Article · Tue Mar 03 00:00:00 EST 2020 · eLife

DOI:https://doi.org/10.7554/elife.53169· OSTI ID:1628916

^[1];

^[2]; Salas, Jordan ^[3]; Rho, Semi ^[1]; Bailey, Justin R. ^[3];

^[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

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.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1628916

Journal Information:: eLife, Vol. 9; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

References (34)

Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody Ying, Tianlei; Prabakaran, Ponraj; Du, Lanying Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms9223	journal	September 2015
iMOSFLM : a new graphical interface for diffraction-image processing with MOSFLM Battye, T. Geoff G.; Kontogiannis, Luke; Johnson, Owen Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910048675	journal	March 2011
Hepatitis C Virus E2 Envelope Glycoprotein Core Structure Kong, L.; Giang, E.; Nieusma, T. Science, Vol. 342, Issue 6162 https://doi.org/10.1126/science.1243876	journal	November 2013
Genotype 1 and global hepatitis C T-cell vaccines designed to optimize coverage of genetic diversity Yusim, K.; Fischer, W.; Yoon, H. Journal of General Virology, Vol. 91, Issue 5 https://doi.org/10.1099/vir.0.017491-0	journal	January 2010
Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles Hsu, M.; Zhang, J.; Flint, M. Proceedings of the National Academy of Sciences, Vol. 100, Issue 12 https://doi.org/10.1073/pnas.0832180100	journal	May 2003
Germline V-genes sculpt the binding site of a family of antibodies neutralizing human cytomegalovirus Thomson, Christy A.; Bryson, Steve; McLean, Gary R. The EMBO Journal, Vol. 27, Issue 19 https://doi.org/10.1038/emboj.2008.179	journal	September 2008
Genetic and structural insights into broad neutralization of hepatitis C virus by human V _H 1-69 antibodies Tzarum, Netanel; Giang, Erick; Kong, Leopold Science Advances, Vol. 5, Issue 1 https://doi.org/10.1126/sciadv.aav1882	journal	January 2019
Somatic insertions and deletions shape the human antibody repertoire 1 1Edited by J. Karn de Wildt, Ruud M. T.; van Venrooij, Walther J.; Winter, Greg Journal of Molecular Biology, Vol. 294, Issue 3 https://doi.org/10.1006/jmbi.1999.3289	journal	December 1999
Neutralizing antibody response during acute and chronic hepatitis C virus infection Logvinoff, C.; Major, M. E.; Oldach, D. Proceedings of the National Academy of Sciences, Vol. 101, Issue 27 https://doi.org/10.1073/pnas.0403519101	journal	June 2004
Breaking the law: unconventional strategies for antibody diversification Kanyavuz, Alexia; Marey-Jarossay, Annaelle; Lacroix-Desmazes, Sébastien Nature Reviews Immunology, Vol. 19, Issue 6 https://doi.org/10.1038/s41577-019-0126-7	journal	February 2019
Broadly neutralizing antibodies from an individual that naturally cleared multiple hepatitis C virus infections uncover molecular determinants for E2 targeting and vaccine design Keck, Zhen-Yong; Pierce, Brian G.; Lau, Patrick PLOS Pathogens, Vol. 15, Issue 5 https://doi.org/10.1371/journal.ppat.1007772	journal	May 2019
abYsis: Integrated Antibody Sequence and Structure—Management, Analysis, and Prediction Swindells, Mark B.; Porter, Craig T.; Couch, Matthew Journal of Molecular Biology, Vol. 429, Issue 3 https://doi.org/10.1016/j.jmb.2016.08.019	journal	February 2017
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Somatic Hypermutation Introduces Insertions and Deletions into Immunoglobulin V Genes Wilson, Patrick C.; Bouteiller, Odette de; Liu, Yong-Jun Journal of Experimental Medicine, Vol. 187, Issue 1 https://doi.org/10.1084/jem.187.1.59	journal	January 1998
VH1-69 antiviral broadly neutralizing antibodies: genetics, structures, and relevance to rational vaccine design Chen, Fang; Tzarum, Netanel; Wilson, Ian A. Current Opinion in Virology, Vol. 34 https://doi.org/10.1016/j.coviro.2019.02.004	journal	February 2019
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Structure and Function of the Hepatitis C Virus Envelope Glycoproteins E1 and E2: Antiviral and Vaccine Targets Freedman, Holly; Logan, Michael R.; Law, John Lok Man ACS Infectious Diseases, Vol. 2, Issue 11 https://doi.org/10.1021/acsinfecdis.6b00110	journal	August 2016
Increases in Acute Hepatitis C Virus Infection Related to a Growing Opioid Epidemic and Associated Injection Drug Use, United States, 2004 to 2014 Zibbell, Jon E.; Asher, Alice K.; Patel, Rajiv C. American Journal of Public Health, Vol. 108, Issue 2 https://doi.org/10.2105/AJPH.2017.304132	journal	February 2018
Immunoglobulin Gene Insertions and Deletions in the Affinity Maturation of HIV-1 Broadly Reactive Neutralizing Antibodies Kepler, Thomas B.; Liao, Hua-Xin; Alam, S. Munir Cell Host & Microbe, Vol. 16, Issue 3 https://doi.org/10.1016/j.chom.2014.08.006	journal	September 2014
Selection Pressure From Neutralizing Antibodies Drives Sequence Evolution During Acute Infection With Hepatitis C Virus Dowd, Kimberly A.; Netski, Dale M.; Wang, Xiao–Hong Gastroenterology, Vol. 136, Issue 7 https://doi.org/10.1053/j.gastro.2009.02.080	journal	June 2009
Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses Sui, Jianhua; Hwang, William C.; Perez, Sandra Nature Structural & Molecular Biology, Vol. 16, Issue 3 https://doi.org/10.1038/nsmb.1566	journal	February 2009
HCV Broadly Neutralizing Antibodies Use a CDRH3 Disulfide Motif to Recognize an E2 Glycoprotein Site that Can Be Targeted for Vaccine Design Flyak, Andrew I.; Ruiz, Stormy; Colbert, Michelle D. Cell Host & Microbe, Vol. 24, Issue 5 https://doi.org/10.1016/j.chom.2018.10.009	journal	November 2018
Inference of Macromolecular Assemblies from Crystalline State Krissinel, Evgeny; Henrick, Kim Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.05.022	journal	September 2007
Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge Law, Mansun; Maruyama, Toshiaki; Lewis, Jamie Nature Medicine, Vol. 14, Issue 1 https://doi.org/10.1038/nm1698	journal	December 2007
Clearance of hepatitis C infection is associated with the early appearance of broad neutralizing antibody responses: Hepatology Osburn, William O.; Snider, Anna E.; Wells, Brittany L. Hepatology, Vol. 59, Issue 6 https://doi.org/10.1002/hep.27013	journal	April 2014
(Mid)West Side Story: Acute Hepatitis C Virus Infection and the Opioid Epidemic in the United States Boesecke, Christoph; Rockstroh, Jürgen K. Hepatology, Vol. 69, Issue 4 https://doi.org/10.1002/hep.30290	journal	February 2019
Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion Benton, Donald J.; Wrobel, Antoni G.; Xu, Pengqi Nature, Vol. 588, Issue 7837 https://doi.org/10.1038/s41586-020-2772-0	journal	September 2020
How good are my data and what is the resolution? Evans, Philip R.; Murshudov, Garib N. Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7 https://doi.org/10.1107/s0907444913000061	journal	June 2013
Exceptionally Potent Neutralization of Middle East Respiratory Syndrome Coronavirus by Human Monoclonal Antibodies Ying, Tianlei; Du, Lanying; Ju, Tina W. Journal of Virology, Vol. 88, Issue 14 https://doi.org/10.1128/jvi.00912-14	journal	April 2014
Computational Reconstruction of Bole1a, a Representative Synthetic Hepatitis C Virus Subtype 1a Genome Munshaw, S.; Bailey, J. R.; Liu, L. Journal of Virology, Vol. 86, Issue 10 https://doi.org/10.1128/jvi.05959-11	journal	March 2012
An Insertion Mutation That Distorts Antibody Binding Site Architecture Enhances Function of a Human Antibody Krause, Jens C.; Ekiert, Damian C.; Tumpey, Terrence M. mBio, Vol. 2, Issue 1 https://doi.org/10.1128/mbio.00345-10	journal	February 2011
Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance Bailey, Justin R.; Wasilewski, Lisa N.; Snider, Anna E. Journal of Clinical Investigation, Vol. 125, Issue 1 https://doi.org/10.1172/jci78794	journal	December 2014
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010

Similar Records

Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals

Journal Article · Wed Jun 08 00:00:00 EDT 2022 · Nature Communications · OSTI ID:1628916

Bozhanova, Nina G.; Flyak, Andrew I.; Brown, Benjamin P.; +10 more

Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization

Journal Article · Wed Jan 05 00:00:00 EST 2022 · Immunity · OSTI ID:1628916

Weber, Timm; Potthoff, Julian; Bizu, Sven; +22 more

Identification of a Novel Drug Lead That Inhibits HCV Infection and Cell-to-Cell Transmission by Targeting the HCV E2 Glycoprotein

Journal Article · Thu Oct 30 00:00:00 EDT 2014 · PLoS ONE · OSTI ID:1628916

Al Olaby, Reem R.; Cocquerel, Laurence; Zemla, Adam; +12 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Life Sciences & Biomedicine - Other Topics

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

Citation Formats

References (34)

Similar Records

Related Subjects