Multiscale affinity maturation simulations to elicit broadly neutralizing antibodies against HIV

Simone Conti; Victor Ovchinnikov; Jonathan G. Faris; Arup K. Chakraborty; Martin Karplus; Kayla G. Sprenger

doi:10.1371/journal.pcbi.1009391

Multiscale affinity maturation simulations to elicit broadly neutralizing antibodies against HIV

Simone Conti
, Victor Ovchinnikov
, Jonathan G. Faris
, Arup K. Chakraborty
, Martin Karplus
, Kayla G. Sprenger

Harvard
University of Colorado Boulder
Massachusetts Institute of Technology
University Louis Pasteur

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

The design of vaccines against highly mutable pathogens, such as HIV and influenza, requires a detailed understanding of how the adaptive immune system responds to encountering multiple variant antigens (Ags). Here, we describe a multiscale model of B cell receptor (BCR) affinity maturation that employs actual BCR nucleotide sequences and treats BCR/Ag interactions in atomistic detail. We apply the model to simulate the maturation of a broadly neutralizing Ab (bnAb) against HIV. Starting from a germline precursor sequence of the VRC01 anti-HIV Ab, we simulate BCR evolution in response to different vaccination protocols and different Ags, which were previously designed by us. The simulation results provide qualitative guidelines for future vaccine design and reveal unique insights into bnAb evolution against the CD4 binding site of HIV. Our model makes possible direct comparisons of simulated BCR populations with results of deep sequencing data, which will be explored in future applications.

Original language	English
Article number	e1009391
Journal	PLoS Computational Biology
Volume	18
Issue number	4
DOIs	https://doi.org/10.1371/journal.pcbi.1009391
State	Published - Apr 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
Copyright: © 2022 Conti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding

Financial support was provided by Lawrence Livermore National Laboratory under Grant 17-ERD-043 (LLC Award B620960; K.G.S and A.K.C), by the Ragon Institute of MGH, MIT, and Harvard University (K.G.S and A.K.C), and by the CHARMM Development Project (M.K., S.C., and V.O.). The funders had no role in study design,

Funders	Funder number
CHARMM Development Project
Ragon Institute of MGH, MIT, and Harvard University
Lawrence Livermore National Laboratory	17-ERD-043, B620960

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1371/journal.pcbi.1009391

Cite this

@article{8845698566fb466bb14dd97e2fca0ad6,

title = "Multiscale affinity maturation simulations to elicit broadly neutralizing antibodies against HIV",

abstract = "The design of vaccines against highly mutable pathogens, such as HIV and influenza, requires a detailed understanding of how the adaptive immune system responds to encountering multiple variant antigens (Ags). Here, we describe a multiscale model of B cell receptor (BCR) affinity maturation that employs actual BCR nucleotide sequences and treats BCR/Ag interactions in atomistic detail. We apply the model to simulate the maturation of a broadly neutralizing Ab (bnAb) against HIV. Starting from a germline precursor sequence of the VRC01 anti-HIV Ab, we simulate BCR evolution in response to different vaccination protocols and different Ags, which were previously designed by us. The simulation results provide qualitative guidelines for future vaccine design and reveal unique insights into bnAb evolution against the CD4 binding site of HIV. Our model makes possible direct comparisons of simulated BCR populations with results of deep sequencing data, which will be explored in future applications.",

author = "Simone Conti and Victor Ovchinnikov and Faris, \{Jonathan G.\} and Chakraborty, \{Arup K.\} and Martin Karplus and Sprenger, \{Kayla G.\}",

note = "Publisher Copyright: Copyright: {\textcopyright} 2022 Conti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2022",

month = apr,

doi = "10.1371/journal.pcbi.1009391",

language = "אנגלית",

volume = "18",

journal = "PLoS Computational Biology",

issn = "1553-734X",

publisher = "Public Library of Science",

number = "4",

}

TY - JOUR

T1 - Multiscale affinity maturation simulations to elicit broadly neutralizing antibodies against HIV

AU - Conti, Simone

AU - Ovchinnikov, Victor

AU - Faris, Jonathan G.

AU - Chakraborty, Arup K.

AU - Karplus, Martin

AU - Sprenger, Kayla G.

N1 - Publisher Copyright: Copyright: © 2022 Conti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2022/4

Y1 - 2022/4

N2 - The design of vaccines against highly mutable pathogens, such as HIV and influenza, requires a detailed understanding of how the adaptive immune system responds to encountering multiple variant antigens (Ags). Here, we describe a multiscale model of B cell receptor (BCR) affinity maturation that employs actual BCR nucleotide sequences and treats BCR/Ag interactions in atomistic detail. We apply the model to simulate the maturation of a broadly neutralizing Ab (bnAb) against HIV. Starting from a germline precursor sequence of the VRC01 anti-HIV Ab, we simulate BCR evolution in response to different vaccination protocols and different Ags, which were previously designed by us. The simulation results provide qualitative guidelines for future vaccine design and reveal unique insights into bnAb evolution against the CD4 binding site of HIV. Our model makes possible direct comparisons of simulated BCR populations with results of deep sequencing data, which will be explored in future applications.

AB - The design of vaccines against highly mutable pathogens, such as HIV and influenza, requires a detailed understanding of how the adaptive immune system responds to encountering multiple variant antigens (Ags). Here, we describe a multiscale model of B cell receptor (BCR) affinity maturation that employs actual BCR nucleotide sequences and treats BCR/Ag interactions in atomistic detail. We apply the model to simulate the maturation of a broadly neutralizing Ab (bnAb) against HIV. Starting from a germline precursor sequence of the VRC01 anti-HIV Ab, we simulate BCR evolution in response to different vaccination protocols and different Ags, which were previously designed by us. The simulation results provide qualitative guidelines for future vaccine design and reveal unique insights into bnAb evolution against the CD4 binding site of HIV. Our model makes possible direct comparisons of simulated BCR populations with results of deep sequencing data, which will be explored in future applications.

UR - https://www.scopus.com/pages/publications/85128793049

U2 - 10.1371/journal.pcbi.1009391

DO - 10.1371/journal.pcbi.1009391

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 35442968

AN - SCOPUS:85128793049

SN - 1553-734X

VL - 18

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 4

M1 - e1009391

ER -

Multiscale affinity maturation simulations to elicit broadly neutralizing antibodies against HIV

Abstract

Bibliographical note

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this