Abstract
Broadly neutralizing antibodies (bnAbs) targeting the HIV envelope glycoprotein (Env) typically take years to develop. Longitudinal analyses of both neutralizing antibody lineages and viruses at serial time points during infection provide a basis for understanding the co-evolutionary contest between HIV and the humoral immune system. Here, we describe the structural characterization of an apex-targeting antibody lineage and autologous clade A viral Env from a donor in the Protocol C cohort. Comparison of Ab-Env complexes at early and late time points reveals that, within the antibody lineage, the CDRH3 loop rigidifies, the bnAb angle of approach steepens, and surface charges are mutated to accommodate glycan changes. Additionally, we observed differences in site-specific glycosylation between soluble and full-length Env constructs, which may be important for tuning optimal immunogenicity in soluble Env trimers. These studies therefore provide important guideposts for design of immunogens that prime and mature nAb responses to the Env V2-apex. Rantalainen et al. describe the structural co-evolution of HIV envelope glycoprotein and antibody response in a single donor from the Protocol C cohort. The co-evolutionary mechanisms include antibody binding angle maturation, gradual loop rigidification, surface charge modulation, and changes in glycan contacts.
Original language | English |
---|---|
Pages (from-to) | 3249-3261 |
Number of pages | 13 |
Journal | Cell reports |
Volume | 23 |
Issue number | 11 |
DOIs | |
Publication status | Published - 12 Jun 2018 |
Keywords
- HIV
- Protocol C
- broadly neutralizing antibody
- cryo-EM
- evolution
- structure
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In: Cell reports, Vol. 23, No. 11, 12.06.2018, p. 3249-3261.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Co-evolution of HIV Envelope and Apex-Targeting Neutralizing Antibody Lineage Provides Benchmarks for Vaccine Design
AU - Rantalainen, Kimmo
AU - Berndsen, Zachary T.
AU - Murrell, Sasha
AU - Cao, Liwei
AU - Omorodion, Oluwarotimi
AU - Torres, Jonathan L.
AU - Wu, Mengyu
AU - Umotoy, Jeffrey
AU - Copps, Jeffrey
AU - Poignard, Pascal
AU - Landais, Elise
AU - Paulson, James C.
AU - Wilson, Ian A.
AU - Ward, Andrew B.
N1 - Funding Information: We thank Hannah Turner, Travis Nieusma, and Bill Anderson for assistance with microscope management, IAVI Protocol C and associated investigators for providing access to sample collection, and Gabe Ozorowski and Lauren Holden for critical reading of the manuscript. This work was supported by NIH grant UM1 AI100663 (Scripps CHAVI-ID), the International AIDS Vaccine Initiative Neutralizing Antibody Center, and the Collaboration for AIDS Vaccine Discovery OPP1115782 and OPP1084519 (Bill and Melinda Gates Foundation). This work was partially funded by IAVI with the generous support of USAID, the Ministry of Foreign Affairs of the Netherlands, and the Bill and Melinda Gates Foundation; a full list of IAVI donors is available at http://www.iavi.org. The contents of this manuscript are the responsibility of the authors and do not necessarily reflect the views of USAID or the US Government. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or the NIH. This research also used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. Funding Information: We thank Hannah Turner, Travis Nieusma, and Bill Anderson for assistance with microscope management, IAVI Protocol C and associated investigators for providing access to sample collection, and Gabe Ozorowski and Lauren Holden for critical reading of the manuscript. This work was supported by NIH grant UM1 AI100663 (Scripps CHAVI-ID), the International AIDS Vaccine Initiative Neutralizing Antibody Center , and the Collaboration for AIDS Vaccine Discovery OPP1115782 and OPP1084519 ( Bill and Melinda Gates Foundation ). This work was partially funded by IAVI with the generous support of USAID , the Ministry of Foreign Affairs of the Netherlands , and the Bill and Melinda Gates Foundation ; a full list of IAVI donors is available at http://www.iavi.org . The contents of this manuscript are the responsibility of the authors and do not necessarily reflect the views of USAID or the US Government. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy , Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515 . The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH, National Institute of General Medical Sciences (including P41GM103393 ). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or the NIH. This research also used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357 . Publisher Copyright: © 2018 The Authors
PY - 2018/6/12
Y1 - 2018/6/12
N2 - Broadly neutralizing antibodies (bnAbs) targeting the HIV envelope glycoprotein (Env) typically take years to develop. Longitudinal analyses of both neutralizing antibody lineages and viruses at serial time points during infection provide a basis for understanding the co-evolutionary contest between HIV and the humoral immune system. Here, we describe the structural characterization of an apex-targeting antibody lineage and autologous clade A viral Env from a donor in the Protocol C cohort. Comparison of Ab-Env complexes at early and late time points reveals that, within the antibody lineage, the CDRH3 loop rigidifies, the bnAb angle of approach steepens, and surface charges are mutated to accommodate glycan changes. Additionally, we observed differences in site-specific glycosylation between soluble and full-length Env constructs, which may be important for tuning optimal immunogenicity in soluble Env trimers. These studies therefore provide important guideposts for design of immunogens that prime and mature nAb responses to the Env V2-apex. Rantalainen et al. describe the structural co-evolution of HIV envelope glycoprotein and antibody response in a single donor from the Protocol C cohort. The co-evolutionary mechanisms include antibody binding angle maturation, gradual loop rigidification, surface charge modulation, and changes in glycan contacts.
AB - Broadly neutralizing antibodies (bnAbs) targeting the HIV envelope glycoprotein (Env) typically take years to develop. Longitudinal analyses of both neutralizing antibody lineages and viruses at serial time points during infection provide a basis for understanding the co-evolutionary contest between HIV and the humoral immune system. Here, we describe the structural characterization of an apex-targeting antibody lineage and autologous clade A viral Env from a donor in the Protocol C cohort. Comparison of Ab-Env complexes at early and late time points reveals that, within the antibody lineage, the CDRH3 loop rigidifies, the bnAb angle of approach steepens, and surface charges are mutated to accommodate glycan changes. Additionally, we observed differences in site-specific glycosylation between soluble and full-length Env constructs, which may be important for tuning optimal immunogenicity in soluble Env trimers. These studies therefore provide important guideposts for design of immunogens that prime and mature nAb responses to the Env V2-apex. Rantalainen et al. describe the structural co-evolution of HIV envelope glycoprotein and antibody response in a single donor from the Protocol C cohort. The co-evolutionary mechanisms include antibody binding angle maturation, gradual loop rigidification, surface charge modulation, and changes in glycan contacts.
KW - HIV
KW - Protocol C
KW - broadly neutralizing antibody
KW - cryo-EM
KW - evolution
KW - structure
UR - http://www.scopus.com/inward/record.url?scp=85048213508&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.celrep.2018.05.046
DO - https://doi.org/10.1016/j.celrep.2018.05.046
M3 - Article
C2 - 29898396
SN - 2211-1247
VL - 23
SP - 3249
EP - 3261
JO - Cell reports
JF - Cell reports
IS - 11
ER -