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Title: Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor

Abstract

VRC01-class antibodies neutralize diverse HIV-1 strains by targeting the conserved CD4-binding site. Despite extensive investigations, crucial events in the early stage of VRC01 development remain elusive. We demonstrated how VRC01-class antibodies emerged in a Chinese donor by antigen-specific single B cell sorting, structural and functional studies, and longitudinal antibody and virus repertoire analyses. A monoclonal antibody DRVIA7 with modest neutralizing breadth was isolated that displayed a subset of VRC01 signatures. X-ray and EM structures revealed a VRC01-like angle of approach, but less favorable interactions between the DRVIA7 light-chain CDR1 and the N terminus with N276 and V5 glycans of gp120. Although the DRVIA7 lineage was unable to acquire broad neutralization, longitudinal analysis revealed a repertoire-encoded VRC01 light-chain CDR3 signature and VRC01-like neutralizing heavy-chain precursors that rapidly matured within 2 years. Furthermore, light chain accommodation of the glycan shield should be taken into account in vaccine design targeting this conserved site of vulnerability.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); NIH NIGMS; SKLID Development; NIH NIAID; NIH CIPRA
OSTI Identifier:
1352095
Alternate Identifier(s):
OSTI ID: 1252759
Grant/Contract Number:  
AC02-06CH11357; U54 GM094586; 2012SKLID103; R01 AI102766; AI084817; P30AI36214; U19AI51915; 2012ZX10001008; UM1 AI100663; P01 AI110657
Resource Type:
Published Article
Journal Name:
Immunity
Additional Journal Information:
Journal Name: Immunity Journal Volume: 44 Journal Issue: 4; Journal ID: ISSN 1074-7613
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; antibody maturation; B cell development; broadly neutralizing antibodies; CD4-binding site; HIV infection; glycan shield; gp120; rational vaccine design; virus-host co-evolution; VRC01 class

Citation Formats

Kong, Leopold, Ju, Bin, Chen, Yajing, He, Linling, Ren, Li, Liu, Jiandong, Hong, Kunxue, Su, Bin, Wang, Zheng, Ozorowski, Gabriel, Ji, Xiaolin, Hua, Yuanzi, Chen, Yanli, Deller, Marc C., Hao, Yanling, Feng, Yi, Garces, Fernando, Wilson, Richard, Dai, Kaifan, O’Dell, Sijy, McKee, Krisha, Mascola, John R., Ward, Andrew B., Wyatt, Richard T., Li, Yuxing, Wilson, Ian A., Zhu, Jiang, and Shao, Yiming. Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor. United States: N. p., 2016. Web. doi:10.1016/j.immuni.2016.03.006.
Kong, Leopold, Ju, Bin, Chen, Yajing, He, Linling, Ren, Li, Liu, Jiandong, Hong, Kunxue, Su, Bin, Wang, Zheng, Ozorowski, Gabriel, Ji, Xiaolin, Hua, Yuanzi, Chen, Yanli, Deller, Marc C., Hao, Yanling, Feng, Yi, Garces, Fernando, Wilson, Richard, Dai, Kaifan, O’Dell, Sijy, McKee, Krisha, Mascola, John R., Ward, Andrew B., Wyatt, Richard T., Li, Yuxing, Wilson, Ian A., Zhu, Jiang, & Shao, Yiming. Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor. United States. doi:10.1016/j.immuni.2016.03.006.
Kong, Leopold, Ju, Bin, Chen, Yajing, He, Linling, Ren, Li, Liu, Jiandong, Hong, Kunxue, Su, Bin, Wang, Zheng, Ozorowski, Gabriel, Ji, Xiaolin, Hua, Yuanzi, Chen, Yanli, Deller, Marc C., Hao, Yanling, Feng, Yi, Garces, Fernando, Wilson, Richard, Dai, Kaifan, O’Dell, Sijy, McKee, Krisha, Mascola, John R., Ward, Andrew B., Wyatt, Richard T., Li, Yuxing, Wilson, Ian A., Zhu, Jiang, and Shao, Yiming. Fri . "Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor". United States. doi:10.1016/j.immuni.2016.03.006.
@article{osti_1352095,
title = {Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor},
author = {Kong, Leopold and Ju, Bin and Chen, Yajing and He, Linling and Ren, Li and Liu, Jiandong and Hong, Kunxue and Su, Bin and Wang, Zheng and Ozorowski, Gabriel and Ji, Xiaolin and Hua, Yuanzi and Chen, Yanli and Deller, Marc C. and Hao, Yanling and Feng, Yi and Garces, Fernando and Wilson, Richard and Dai, Kaifan and O’Dell, Sijy and McKee, Krisha and Mascola, John R. and Ward, Andrew B. and Wyatt, Richard T. and Li, Yuxing and Wilson, Ian A. and Zhu, Jiang and Shao, Yiming},
abstractNote = {VRC01-class antibodies neutralize diverse HIV-1 strains by targeting the conserved CD4-binding site. Despite extensive investigations, crucial events in the early stage of VRC01 development remain elusive. We demonstrated how VRC01-class antibodies emerged in a Chinese donor by antigen-specific single B cell sorting, structural and functional studies, and longitudinal antibody and virus repertoire analyses. A monoclonal antibody DRVIA7 with modest neutralizing breadth was isolated that displayed a subset of VRC01 signatures. X-ray and EM structures revealed a VRC01-like angle of approach, but less favorable interactions between the DRVIA7 light-chain CDR1 and the N terminus with N276 and V5 glycans of gp120. Although the DRVIA7 lineage was unable to acquire broad neutralization, longitudinal analysis revealed a repertoire-encoded VRC01 light-chain CDR3 signature and VRC01-like neutralizing heavy-chain precursors that rapidly matured within 2 years. Furthermore, light chain accommodation of the glycan shield should be taken into account in vaccine design targeting this conserved site of vulnerability.},
doi = {10.1016/j.immuni.2016.03.006},
journal = {Immunity},
number = 4,
volume = 44,
place = {United States},
year = {2016},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1016/j.immuni.2016.03.006

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