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Title: Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies

Abstract

Eliciting antibodies that are cross reactive with surface proteins of diverse strains of highly mutable pathogens (e.g., HIV, influenza) could be key for developing effective universal vaccines. Mutations in the framework regions of such broadly neutralizing antibodies (bnAbs) have been reported to play a role in determining their properties. We used molecular dynamics simulations and models of affinity maturation to study specific bnAbs against HIV. Our results suggest that there are different classes of evolutionary lineages for the bnAbs. If germline B cells that initiate affinity maturation have high affinity for the conserved residues of the targeted epitope, framework mutations increase antibody rigidity as affinity maturation progresses to evolve bnAbs. If the germline B cells exhibit weak/moderate affinity for conserved residues, an initial increase in flexibility via framework mutations may be required for the evolution of bnAbs. Subsequent mutations that increase rigidity result in highly potent bnAbs. Implications of our results for immunogen design are discussed.

Authors:
ORCiD logo [1];  [2]; ORCiD logo [3];  [4]; ORCiD logo [5]
  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
  2. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, United States
  3. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States, Department of Physics, Massachusetts Institute of Technology, Cambridge, United States, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, United States, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
  4. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States, Laboratoire de Chimie Biophysique, ISIS, Universite de Strasbourg, Strasbourg, France
  5. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States, Department of Physics, Massachusetts Institute of Technology, Cambridge, United States, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, United States, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1420455
Alternate Identifier(s):
OSTI ID: 1420456
Grant/Contract Number:  
LLC Award #B620960
Resource Type:
Published Article
Journal Name:
eLife
Additional Journal Information:
Journal Name: eLife Journal Volume: 7; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
English

Citation Formats

Ovchinnikov, Victor, Louveau, Joy E., Barton, John P., Karplus, Martin, and Chakraborty, Arup K. Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies. United States: N. p., 2018. Web. doi:10.7554/eLife.33038.
Ovchinnikov, Victor, Louveau, Joy E., Barton, John P., Karplus, Martin, & Chakraborty, Arup K. Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies. United States. doi:10.7554/eLife.33038.
Ovchinnikov, Victor, Louveau, Joy E., Barton, John P., Karplus, Martin, and Chakraborty, Arup K. Wed . "Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies". United States. doi:10.7554/eLife.33038.
@article{osti_1420455,
title = {Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies},
author = {Ovchinnikov, Victor and Louveau, Joy E. and Barton, John P. and Karplus, Martin and Chakraborty, Arup K.},
abstractNote = {Eliciting antibodies that are cross reactive with surface proteins of diverse strains of highly mutable pathogens (e.g., HIV, influenza) could be key for developing effective universal vaccines. Mutations in the framework regions of such broadly neutralizing antibodies (bnAbs) have been reported to play a role in determining their properties. We used molecular dynamics simulations and models of affinity maturation to study specific bnAbs against HIV. Our results suggest that there are different classes of evolutionary lineages for the bnAbs. If germline B cells that initiate affinity maturation have high affinity for the conserved residues of the targeted epitope, framework mutations increase antibody rigidity as affinity maturation progresses to evolve bnAbs. If the germline B cells exhibit weak/moderate affinity for conserved residues, an initial increase in flexibility via framework mutations may be required for the evolution of bnAbs. Subsequent mutations that increase rigidity result in highly potent bnAbs. Implications of our results for immunogen design are discussed.},
doi = {10.7554/eLife.33038},
journal = {eLife},
number = ,
volume = 7,
place = {United States},
year = {2018},
month = {2}
}

Journal Article:
Free Publicly Available Full Text
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DOI: 10.7554/eLife.33038

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Cited by: 4 works
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Works referenced in this record:

Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans
journal, December 2015


Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo
journal, October 2012

  • Moldt, B.; Rakasz, E. G.; Schultz, N.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 46
  • DOI: 10.1073/pnas.1214785109

Absolute Free-Energy Calculations of Liquids Using a Harmonic Reference State
journal, August 2007

  • Tyka, Michael D.; Sessions, Richard B.; Clarke, Anthony R.
  • The Journal of Physical Chemistry B, Vol. 111, Issue 32
  • DOI: 10.1021/jp072357w

Residue-Level Prediction of HIV-1 Antibody Epitopes Based on Neutralization of Diverse Viral Strains
journal, July 2013

  • Chuang, G. -Y.; Acharya, P.; Schmidt, S. D.
  • Journal of Virology, Vol. 87, Issue 18
  • DOI: 10.1128/JVI.00984-13

Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice
journal, June 2015


Germinal Centers
journal, April 2012


Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies
journal, February 2015


Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains
journal, June 2014

  • Fera, D.; Schmidt, A. G.; Haynes, B. F.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 28
  • DOI: 10.1073/pnas.1409954111

Somatic hypermutation
journal, April 1995


Molecular evolution of affinity and flexibility in the immune system
journal, May 2007

  • Thorpe, I. F.; Brooks, C. L.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 21
  • DOI: 10.1073/pnas.0610064104

Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies
journal, February 2000

  • Mascola, John R.; Stiegler, Gabriela; VanCott, Thomas C.
  • Nature Medicine, Vol. 6, Issue 2
  • DOI: 10.1038/72318

Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding
journal, July 2011


Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes
journal, March 1977

  • Ryckaert, Jean-Paul; Ciccotti, Giovanni; Berendsen, Herman J. C.
  • Journal of Computational Physics, Vol. 23, Issue 3
  • DOI: 10.1016/0021-9991(77)90098-5

Origins of Allostery and Evolvability in Proteins: A Case Study
journal, July 2016


Evolving concepts of specificity in immune reactions
journal, December 2010

  • Eisen, H. N.; Chakraborty, A. K.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 52
  • DOI: 10.1073/pnas.1012051108

Visualizing antibody affinity maturation in germinal centers
journal, February 2016


Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals
journal, March 2009

  • Scheid, Johannes F.; Mouquet, Hugo; Feldhahn, Niklas
  • Nature, Vol. 458, Issue 7238
  • DOI: 10.1038/nature07930

The Imprint of Somatic Hypermutation on the Repertoire of Human Germline V Genes
journal, March 1996

  • Tomlinson, Ian M.; Walter, Gerald; Jones, Peter T.
  • Journal of Molecular Biology, Vol. 256, Issue 5
  • DOI: 10.1006/jmbi.1996.0127

Germinal center selection and the development of memory B and plasma cells: Germinal center differentiation and selection
journal, April 2012


Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors
journal, March 2013


Structural basis for germline antibody recognition of HIV-1 immunogens
journal, March 2016


SKEMPI: a Structural Kinetic and Energetic database of Mutant Protein Interactions and its use in empirical models
journal, August 2012


CHARMM: The biomolecular simulation program
journal, July 2009

  • Brooks, B. R.; Brooks, C. L.; Mackerell, A. D.
  • Journal of Computational Chemistry, Vol. 30, Issue 10
  • DOI: 10.1002/jcc.21287

Neutralizing antibodies to HIV-1 induced by immunization
journal, February 2013

  • McCoy, Laura E.; Weiss, Robin A.
  • The Journal of Experimental Medicine, Vol. 210, Issue 2
  • DOI: 10.1084/jem.20121827

Evolutionary and immunological implications of contemporary HIV-1 variation
journal, September 2001


Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus
journal, April 2013

  • Liao, Hua-Xin; Lynch, Rebecca; Zhou, Tongqing
  • Nature, Vol. 496, Issue 7446
  • DOI: 10.1038/nature12053

Effects of somatic mutations on CDR loop flexibility during affinity maturation
journal, December 2010

  • Wong, Sergio E.; Sellers, Ben D.; Jacobson, Matthew P.
  • Proteins: Structure, Function, and Bioinformatics, Vol. 79, Issue 3
  • DOI: 10.1002/prot.22920

Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies
journal, October 2015

  • Bhiman, Jinal N.; Anthony, Colin; Doria-Rose, Nicole A.
  • Nature Medicine, Vol. 21, Issue 11
  • DOI: 10.1038/nm.3963

Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody
journal, April 2016


Somatic Hypermutation of Immunoglobulin Genes
journal, April 1996


bNAber: database of broadly neutralizing HIV antibodies
journal, November 2013

  • Eroshkin, Alexey M.; LeBlanc, Andrew; Weekes, Dana
  • Nucleic Acids Research, Vol. 42, Issue D1
  • DOI: 10.1093/nar/gkt1083

ACEMD: Accelerating Biomolecular Dynamics in the Microsecond Time Scale
journal, May 2009

  • Harvey, M. J.; Giupponi, G.; Fabritiis, G. De
  • Journal of Chemical Theory and Computation, Vol. 5, Issue 6
  • DOI: 10.1021/ct9000685

HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen
journal, March 2016


Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens
journal, October 2016

  • Shaffer, J. Scott; Moore, Penny L.; Kardar, Mehran
  • Proceedings of the National Academy of Sciences, Vol. 113, Issue 45
  • DOI: 10.1073/pnas.1614940113

HIV therapy by a combination of broadly neutralizing antibodies in humanized mice
journal, October 2012

  • Klein, Florian; Halper-Stromberg, Ariel; Horwitz, Joshua A.
  • Nature, Vol. 492, Issue 7427
  • DOI: 10.1038/nature11604

Antigenicity and Immunogenicity in HIV-1 Antibody-Based Vaccine Design
journal, January 2012

  • Kong, Leopold; J. Sattentau, Quentin
  • Journal of AIDS & Clinical Research, Vol. 01, Issue S8
  • DOI: 10.4172/2155-6113.S8-003

Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo
journal, May 2016


gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory
journal, July 1994


Harmonic analysis of large systems. I. Methodology
journal, December 1995

  • Brooks, Bernard R.; Jane?i?, Du?anka; Karplus, Martin
  • Journal of Computational Chemistry, Vol. 16, Issue 12
  • DOI: 10.1002/jcc.540161209

Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice
journal, September 2016


A brief history of T cell help to B cells
journal, February 2015

  • Crotty, Shane
  • Nature Reviews Immunology, Vol. 15, Issue 3
  • DOI: 10.1038/nri3803

Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies
journal, October 2012

  • Mouquet, H.; Scharf, L.; Euler, Z.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 47
  • DOI: 10.1073/pnas.1217207109

Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody
journal, November 2012

  • Schmidt, A. G.; Xu, H.; Khan, A. R.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 1
  • DOI: 10.1073/pnas.1218256109

Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys
journal, October 2013

  • Barouch, Dan H.; Whitney, James B.; Moldt, Brian
  • Nature, Vol. 503, Issue 7475
  • DOI: 10.1038/nature12744

Mutation Drift and Repertoire Shift in the Maturation of the Immune Response
journal, April 1987


Ontogeny of Recognition Specificity and Functionality for the Broadly Neutralizing Anti-HIV Antibody 4E10
journal, September 2014


The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies
journal, November 2013


HIV infection
journal, October 2015

  • Deeks, Steven G.; Overbaugh, Julie; Phillips, Andrew
  • Nature Reviews Disease Primers, Vol. 1, Issue 1
  • DOI: 10.1038/nrdp.2015.35

Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization
journal, March 2013


Molecular dynamics and free-energy calculations applied to affinity maturation in antibody 48G7
journal, December 1999

  • Chong, L. T.; Duan, Y.; Wang, L.
  • Proceedings of the National Academy of Sciences, Vol. 96, Issue 25
  • DOI: 10.1073/pnas.96.25.14330

On the calculation of entropy from covariance matrices of the atomic fluctuations
journal, October 2001

  • Andricioaei, Ioan; Karplus, Martin
  • The Journal of Chemical Physics, Vol. 115, Issue 14
  • DOI: 10.1063/1.1401821

Variations in Affinities of Antibodies during the Immune Response *
journal, July 1964


Conformational isomerism and the diversity of antibodies.
journal, October 1994

  • Foote, J.; Milstein, C.
  • Proceedings of the National Academy of Sciences, Vol. 91, Issue 22
  • DOI: 10.1073/pnas.91.22.10370

Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies
journal, March 2014

  • Doria-Rose, Nicole A.; Schramm, Chaim A.; Gorman, Jason
  • Nature, Vol. 509, Issue 7498
  • DOI: 10.1038/nature13036

Structural Insights into the Evolution of an Antibody Combining Site
journal, June 1997


HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies
journal, September 2016


Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen
journal, June 2015


Imaging of Germinal Center Selection Events During Affinity Maturation
journal, January 2007


Optimality of Mutation and Selection in Germinal Centers
journal, June 2010