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Title: Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies

Abstract

Antibody somatic hypermutation (SHM) and affinity maturation enhance antigen recognition by modifying antibody paratope structure to improve its complementarity with the target epitope. SHM-induced changes in paratope dynamics may also contribute to antibody maturation, but direct evidence of this is limited. Here, we examine two classes of HIV-1 broadly neutralizing antibodies (bNAbs) for SHM-induced changes in structure and dynamics, and delineate the effects of these changes on interactions with the HIV-1 envelope glycoprotein (Env). In combination with new and existing structures of unmutated and affinity matured antibody Fab fragments, we used hydrogen/deuterium exchange with mass spectrometry to directly measure Fab structural dynamics. Changes in antibody structure and dynamics were positioned to improve complementarity with Env, with changes in dynamics primarily observed at the paratope peripheries. Here, we conclude that SHM optimizes paratope complementarity to conserved HIV-1 epitopes and restricts the mobility of paratope-peripheral residues to minimize clashes with variable features on HIV-1 Env.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
OSTI Identifier:
1399030
Alternate Identifier(s):
OSTI ID: 1314263
Grant/Contract Number:  
W-31-109-Eng-38; R01-GM099989; R21-AI112389; T32-AI7509; OPP1033102
Resource Type:
Published Article
Journal Name:
Structure
Additional Journal Information:
Journal Name: Structure Journal Volume: 24 Journal Issue: 8; Journal ID: ISSN 0969-2126
Publisher:
Elsevier
Country of Publication:
United Kingdom
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Davenport, Thaddeus M., Gorman, Jason, Joyce, M. Gordon, Zhou, Tongqing, Soto, Cinque, Guttman, Miklos, Moquin, Stephanie, Yang, Yongping, Zhang, Baoshan, Doria-Rose, Nicole A., Hu, Shiu-Lok, Mascola, John R., Kwong, Peter D., and Lee, Kelly K. Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies. United Kingdom: N. p., 2016. Web. doi:10.1016/j.str.2016.06.012.
Davenport, Thaddeus M., Gorman, Jason, Joyce, M. Gordon, Zhou, Tongqing, Soto, Cinque, Guttman, Miklos, Moquin, Stephanie, Yang, Yongping, Zhang, Baoshan, Doria-Rose, Nicole A., Hu, Shiu-Lok, Mascola, John R., Kwong, Peter D., & Lee, Kelly K. Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies. United Kingdom. doi:10.1016/j.str.2016.06.012.
Davenport, Thaddeus M., Gorman, Jason, Joyce, M. Gordon, Zhou, Tongqing, Soto, Cinque, Guttman, Miklos, Moquin, Stephanie, Yang, Yongping, Zhang, Baoshan, Doria-Rose, Nicole A., Hu, Shiu-Lok, Mascola, John R., Kwong, Peter D., and Lee, Kelly K. Mon . "Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies". United Kingdom. doi:10.1016/j.str.2016.06.012.
@article{osti_1399030,
title = {Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies},
author = {Davenport, Thaddeus M. and Gorman, Jason and Joyce, M. Gordon and Zhou, Tongqing and Soto, Cinque and Guttman, Miklos and Moquin, Stephanie and Yang, Yongping and Zhang, Baoshan and Doria-Rose, Nicole A. and Hu, Shiu-Lok and Mascola, John R. and Kwong, Peter D. and Lee, Kelly K.},
abstractNote = {Antibody somatic hypermutation (SHM) and affinity maturation enhance antigen recognition by modifying antibody paratope structure to improve its complementarity with the target epitope. SHM-induced changes in paratope dynamics may also contribute to antibody maturation, but direct evidence of this is limited. Here, we examine two classes of HIV-1 broadly neutralizing antibodies (bNAbs) for SHM-induced changes in structure and dynamics, and delineate the effects of these changes on interactions with the HIV-1 envelope glycoprotein (Env). In combination with new and existing structures of unmutated and affinity matured antibody Fab fragments, we used hydrogen/deuterium exchange with mass spectrometry to directly measure Fab structural dynamics. Changes in antibody structure and dynamics were positioned to improve complementarity with Env, with changes in dynamics primarily observed at the paratope peripheries. Here, we conclude that SHM optimizes paratope complementarity to conserved HIV-1 epitopes and restricts the mobility of paratope-peripheral residues to minimize clashes with variable features on HIV-1 Env.},
doi = {10.1016/j.str.2016.06.012},
journal = {Structure},
number = 8,
volume = 24,
place = {United Kingdom},
year = {2016},
month = {8}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1016/j.str.2016.06.012

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Cited by: 6 works
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Works referencing / citing this record:

Repertoire Analysis of Antibody CDR-H3 Loops Suggests Affinity Maturation Does Not Typically Result in Rigidification
journal, March 2018