Structural Comparison of Human Anti-HIV-1 gp120 V3 Monoclonal Antibodies of the Same Gene Usage Induced by Vaccination and Chronic Infection
Abstract
ABSTRACT Elucidating the structural basis of antibody (Ab) gene usage and affinity maturation of vaccine-induced Abs can inform the design of immunogens for inducing desired Ab responses in HIV vaccine development. Analyses of monoclonal Abs (MAbs) encoded by the same immunoglobulin genes at different stages of maturation can help to elucidate the maturation process. We have analyzed four human anti-V3 MAbs with the same VH1-3*01 and VL3-10*01 gene usage. Two MAbs, TA6 and TA7, were developed from a vaccinee in the HIV vaccine phase I trial DP6-001 with a polyvalent DNA prime/protein boost regimen, and two others, 311-11D and 1334, were developed from HIV-infected patients. The somatic hypermutation (SHM) rates in VH of vaccine-induced MAbs are lower than in chronic HIV infection-induced MAbs, while those in VL are comparable. Crystal structures of the antigen-binding fragments (Fabs) in complex with V3 peptides show that these MAbs bind the V3 epitope with a new cradle-binding mode and that the V3 β-hairpin lies along the antigen-binding groove, which consists of residues from both heavy and light chains. Residues conserved from the germ line sequences form specific binding pockets accommodating conserved structural elements of the V3 crown hairpin, predetermining the Ab gene selection, whilemore »
- Authors:
- Publication Date:
- Research Org.:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1499610
- Report Number(s):
- BNL-209612-2018-JACI
Journal ID: ISSN 0022-538X
- DOE Contract Number:
- SC0012704
- Resource Type:
- Journal Article
- Journal Name:
- Journal of Virology
- Additional Journal Information:
- Journal Volume: 92; Journal Issue: 18; Journal ID: ISSN 0022-538X
- Publisher:
- American Society for Microbiology
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 36 MATERIALS SCIENCE
Citation Formats
Chan, Kun-Wei, Pan, Ruimin, Costa, Matthew, Gorny, Miroslaw K., Wang, Shixia, Lu, Shan, Kong, Xiang-Peng, and Sundquist, Wesley I. Structural Comparison of Human Anti-HIV-1 gp120 V3 Monoclonal Antibodies of the Same Gene Usage Induced by Vaccination and Chronic Infection. United States: N. p., 2018.
Web. doi:10.1128/JVI.00641-18.
Chan, Kun-Wei, Pan, Ruimin, Costa, Matthew, Gorny, Miroslaw K., Wang, Shixia, Lu, Shan, Kong, Xiang-Peng, & Sundquist, Wesley I. Structural Comparison of Human Anti-HIV-1 gp120 V3 Monoclonal Antibodies of the Same Gene Usage Induced by Vaccination and Chronic Infection. United States. https://doi.org/10.1128/JVI.00641-18
Chan, Kun-Wei, Pan, Ruimin, Costa, Matthew, Gorny, Miroslaw K., Wang, Shixia, Lu, Shan, Kong, Xiang-Peng, and Sundquist, Wesley I. 2018.
"Structural Comparison of Human Anti-HIV-1 gp120 V3 Monoclonal Antibodies of the Same Gene Usage Induced by Vaccination and Chronic Infection". United States. https://doi.org/10.1128/JVI.00641-18.
@article{osti_1499610,
title = {Structural Comparison of Human Anti-HIV-1 gp120 V3 Monoclonal Antibodies of the Same Gene Usage Induced by Vaccination and Chronic Infection},
author = {Chan, Kun-Wei and Pan, Ruimin and Costa, Matthew and Gorny, Miroslaw K. and Wang, Shixia and Lu, Shan and Kong, Xiang-Peng and Sundquist, Wesley I.},
abstractNote = {ABSTRACT Elucidating the structural basis of antibody (Ab) gene usage and affinity maturation of vaccine-induced Abs can inform the design of immunogens for inducing desired Ab responses in HIV vaccine development. Analyses of monoclonal Abs (MAbs) encoded by the same immunoglobulin genes at different stages of maturation can help to elucidate the maturation process. We have analyzed four human anti-V3 MAbs with the same VH1-3*01 and VL3-10*01 gene usage. Two MAbs, TA6 and TA7, were developed from a vaccinee in the HIV vaccine phase I trial DP6-001 with a polyvalent DNA prime/protein boost regimen, and two others, 311-11D and 1334, were developed from HIV-infected patients. The somatic hypermutation (SHM) rates in VH of vaccine-induced MAbs are lower than in chronic HIV infection-induced MAbs, while those in VL are comparable. Crystal structures of the antigen-binding fragments (Fabs) in complex with V3 peptides show that these MAbs bind the V3 epitope with a new cradle-binding mode and that the V3 β-hairpin lies along the antigen-binding groove, which consists of residues from both heavy and light chains. Residues conserved from the germ line sequences form specific binding pockets accommodating conserved structural elements of the V3 crown hairpin, predetermining the Ab gene selection, while somatically mutated residues create additional hydrogen bonds, electrostatic interactions, and van der Waals contacts, correlating with an increased binding affinity. Our data provide a unique example of germ line sequences determining the primordial antigen-binding sites and SHMs correlating with affinity maturation of Abs induced by vaccine and natural HIV infection. IMPORTANCEUnderstanding the structural basis of gene usage and affinity maturation for anti-HIV-1 antibodies may help vaccine design and development. Antibodies targeting the highly immunogenic third variable loop (V3) of HIV-1 gp120 provide a unique opportunity for detailed structural investigations. By comparing the sequences and structures of four anti-V3 MAbs at different stages of affinity maturation but of the same V gene usage, two induced by vaccination and another two by chronic infection, we provide a fine example of how germ line sequence determines the essential elements for epitope recognition and how affinity maturation improves the antibody's recognition of its epitope.},
doi = {10.1128/JVI.00641-18},
url = {https://www.osti.gov/biblio/1499610},
journal = {Journal of Virology},
issn = {0022-538X},
number = 18,
volume = 92,
place = {United States},
year = {Wed Jul 11 00:00:00 EDT 2018},
month = {Wed Jul 11 00:00:00 EDT 2018}
}
Works referenced in this record:
Crystal Structures of Human Immunodeficiency Virus Type 1 (HIV-1) Neutralizing Antibody 2219 in Complex with Three Different V3 Peptides Reveal a New Binding Mode for HIV-1 Cross-Reactivity
journal, May 2006
- Stanfield, R. L.; Gorny, M. K.; Zolla-Pazner, S.
- Journal of Virology, Vol. 80, Issue 12
Anti-V3 Monoclonal Antibodies Display Broad Neutralizing Activities against Multiple HIV-1 Subtypes
journal, April 2010
- Hioe, Catarina E.; Wrin, Terri; Seaman, Michael S.
- PLoS ONE, Vol. 5, Issue 4
SuperPose: a simple server for sophisticated structural superposition
journal, July 2004
- Maiti, R.; Van Domselaar, G. H.; Zhang, H.
- Nucleic Acids Research, Vol. 32, Issue Web Server
Construction and testing of mouse--human heteromyelomas for human monoclonal antibody production.
journal, December 1983
- Teng, N. N.; Lam, K. S.; Calvo Riera, F.
- Proceedings of the National Academy of Sciences, Vol. 80, Issue 23
Generation of human monoclonal antibodies to human immunodeficiency virus.
journal, March 1989
- Gorny, M. K.; Gianakakos, V.; Sharpe, S.
- Proceedings of the National Academy of Sciences, Vol. 86, Issue 5
The Emerging Importance of IgG Fab Glycosylation in Immunity
journal, February 2016
- van de Bovenkamp, Fleur S.; Hafkenscheid, Lise; Rispens, Theo
- The Journal of Immunology, Vol. 196, Issue 4
Structure of Antibody F425-B4e8 in Complex with a V3 Peptide Reveals a New Binding Mode for HIV-1 Neutralization
journal, January 2008
- Bell, Christian H.; Pantophlet, Ralph; Schiefner, André
- Journal of Molecular Biology, Vol. 375, Issue 4
Different Pattern of Immunoglobulin Gene Usage by HIV-1 Compared to Non-HIV-1 Antibodies Derived from the Same Infected Subject
journal, June 2012
- Li, Liuzhe; Wang, Xiao-Hong; Banerjee, Sagarika
- PLoS ONE, Vol. 7, Issue 6
X-ray snapshots of the maturation of an antibody response to a protein antigen
journal, May 2003
- Li, Yili; Li, Hongmin; Yang, Feng
- Nature Structural & Molecular Biology, Vol. 10, Issue 6
Structural analysis of affinity maturation: The three-dimensional structures of complexes of an anti-nitrophenol antibody
journal, October 1995
- Yuhasz, Stacieann C.; Parry, Christian; Strand, Mette
- Molecular Immunology, Vol. 32, Issue 14-15
Structural mechanism for affinity maturation of an anti-lysozyme antibody
journal, February 2004
- Cauerhff, A.; Goldbaum, F. A.; Braden, B. C.
- Proceedings of the National Academy of Sciences, Vol. 101, Issue 10
A broad range of mutations in HIV-1 neutralizing human monoclonal antibodies specific for V2, V3, and the CD4 binding site
journal, August 2015
- Li, Liuzhe; Wang, Xiao-Hong; Williams, Constance
- Molecular Immunology, Vol. 66, Issue 2
Structural Rationale for the Broad Neutralization of HIV-1 by Human Monoclonal Antibody 447-52D
journal, February 2004
- Stanfield, Robyn L.; Gorny, Miroslaw K.; Williams, Constance
- Structure, Vol. 12, Issue 2
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
Kinetic maturation of an immune response
journal, August 1991
- Foote, Jefferson; Milstein, César
- Nature, Vol. 352, Issue 6335
Structures of the CCR5 N Terminus and of a Tyrosine-Sulfated Antibody with HIV-1 gp120 and CD4
journal, September 2007
- Huang, C. -c.; Lam, S. N.; Acharya, P.
- Science, Vol. 317, Issue 5846
Human Anti-V3 HIV-1 Monoclonal Antibodies Encoded by the VH5-51/VL Lambda Genes Define a Conserved Antigenic Structure
journal, December 2011
- Gorny, Miroslaw K.; Sampson, Jared; Li, Huiguang
- PLoS ONE, Vol. 6, Issue 12
HIV-1 Entry Cofactor: Functional cDNA Cloning of a Seven-Transmembrane, G Protein-Coupled Receptor
journal, May 1996
- Feng, Y.; Broder, C. C.; Kennedy, P. E.
- Science, Vol. 272, Issue 5263
Structure of a V3-Containing HIV-1 gp120 Core
journal, November 2005
- Huang, C. -c.
- Science, Vol. 310, Issue 5750
Effects of Oligomerization on the Epitopes of the Human Immunodeficiency Virus Type 1 Envelope Glycoproteins
journal, February 2000
- Gorny, Miroslaw K.; VanCott, Thomas C.; Williams, Constance
- Virology, Vol. 267, Issue 2
Three-dimensional Structures of the Fab Fragment of Murine N1G9 Antibody from the Primary Immune Response and of its Complex with (4-Hydroxy-3-Nitrophenyl)acetate
journal, November 1995
- Mizutani, Ryuta; Miura, Keiko; Nakayama, Tomonori
- Journal of Molecular Biology, Vol. 254, Issue 2
Insights into the Structural Basis of Antibody Affinity Maturation from Next-Generation Sequencing
journal, February 2018
- Mishra, Arjun K.; Mariuzza, Roy A.
- Frontiers in Immunology, Vol. 9
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
Identification of a major co-receptor for primary isolates of HIV-1
journal, June 1996
- Deng, HongKui; Liu, Rong; Ellmeier, Wilfried
- Nature, Vol. 381, Issue 6584
Crystal structure of a human immunodeficiency virus type 1 neutralizing antibody, 50.1, in complex with its V3 loop peptide antigen.
journal, July 1993
- Rini, J. M.; Stanfield, R. L.; Stura, E. A.
- Proceedings of the National Academy of Sciences, Vol. 90, Issue 13
Crystal Structure of a Soluble Cleaved HIV-1 Envelope Trimer
journal, October 2013
- Julien, J. -P.; Cupo, A.; Sok, D.
- Science, Vol. 342, Issue 6165
Somatic generation of antibody diversity
journal, April 1983
- Tonegawa, Susumu
- Nature, Vol. 302, Issue 5909
Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001
journal, September 2016
- Costa, Matthew R.; Pollara, Justin; Edwards, Regina Whitney
- Journal of Virology, Vol. 90, Issue 22
Autoreactivity in Human IgG+ Memory B Cells
journal, February 2007
- Tiller, Thomas; Tsuiji, Makoto; Yurasov, Sergey
- Immunity, Vol. 26, Issue 2
Variations in Affinities of Antibodies during the Immune Response *
journal, July 1964
- Eisen, Herman N.; Siskind, Gregory W.
- Biochemistry, Vol. 3, Issue 7
HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5
journal, June 1996
- Dragic, Tatjana; Litwin, Virginia; Allaway, Graham P.
- Nature, Vol. 381, Issue 6584
Conserved structural elements in the V3 crown of HIV-1 gp120
journal, July 2010
- Jiang, Xunqing; Burke, Valicia; Totrov, Maxim
- Nature Structural & Molecular Biology, Vol. 17, Issue 8
Structural Insights into the Evolution of an Antibody Combining Site
journal, June 1997
- Wedemayer, G. J.
- Science, Vol. 276, Issue 5319
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
Thermodynamic Signatures of the Antigen Binding Site of mAb 447–52D Targeting the Third Variable Region of HIV-1 gp120
journal, August 2013
- Killikelly, April; Zhang, Hui-Tang; Spurrier, Brett
- Biochemistry, Vol. 52, Issue 36
Preferential use of the VH5-51 gene segment by the human immune response to code for antibodies against the V3 domain of HIV-1
journal, February 2009
- Gorny, Miroslaw K.; Wang, Xiao-Hong; Williams, Constance
- Molecular Immunology, Vol. 46, Issue 5
Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers
journal, July 2008
- Wang, Shixia; Kennedy, Jeffrey S.; West, Kim
- Vaccine, Vol. 26, Issue 31
Structural Basis of the Cross-Reactivity of Genetically Related Human Anti-HIV-1 mAbs: Implications for Design of V3-Based Immunogens
journal, November 2009
- Burke, Valicia; Williams, Constance; Sukumaran, Madhav
- Structure, Vol. 17, Issue 11
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4