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A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies
HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germ line-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-ex...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973348/ https://www.ncbi.nlm.nih.gov/pubmed/36629414 http://dx.doi.org/10.1128/mbio.03370-22 |
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author | Bibollet-Ruche, Frederic Russell, Ronnie M. Ding, Wenge Liu, Weimin Li, Yingying Wagh, Kshitij Wrapp, Daniel Habib, Rumi Skelly, Ashwin N. Roark, Ryan S. Sherrill-Mix, Scott Wang, Shuyi Rando, Juliette Lindemuth, Emily Cruickshank, Kendra Park, Younghoon Baum, Rachel Carey, John W. Connell, Andrew Jesse Li, Hui Giorgi, Elena E. Song, Ge S. Ding, Shilei Finzi, Andrés Newman, Amanda Hernandez, Giovanna E. Machiele, Emily Cain, Derek W. Mansouri, Katayoun Lewis, Mark G. Montefiori, David C. Wiehe, Kevin J. Alam, S. Munir Teng, I-Ting Kwong, Peter D. Andrabi, Raiees Verkoczy, Laurent Burton, Dennis R. Korber, Bette T. Saunders, Kevin O. Haynes, Barton F. Edwards, Robert J. Shaw, George M. Hahn, Beatrice H. |
author_facet | Bibollet-Ruche, Frederic Russell, Ronnie M. Ding, Wenge Liu, Weimin Li, Yingying Wagh, Kshitij Wrapp, Daniel Habib, Rumi Skelly, Ashwin N. Roark, Ryan S. Sherrill-Mix, Scott Wang, Shuyi Rando, Juliette Lindemuth, Emily Cruickshank, Kendra Park, Younghoon Baum, Rachel Carey, John W. Connell, Andrew Jesse Li, Hui Giorgi, Elena E. Song, Ge S. Ding, Shilei Finzi, Andrés Newman, Amanda Hernandez, Giovanna E. Machiele, Emily Cain, Derek W. Mansouri, Katayoun Lewis, Mark G. Montefiori, David C. Wiehe, Kevin J. Alam, S. Munir Teng, I-Ting Kwong, Peter D. Andrabi, Raiees Verkoczy, Laurent Burton, Dennis R. Korber, Bette T. Saunders, Kevin O. Haynes, Barton F. Edwards, Robert J. Shaw, George M. Hahn, Beatrice H. |
author_sort | Bibollet-Ruche, Frederic |
collection | PubMed |
description | HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germ line-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-expressing knock-in mice and as chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) in rhesus macaques (RMs). Trimer immunization of knock-in mice induced V2-directed NAbs, indicating activation of V2-apex bNAb precursor-expressing mouse B cells. SCIV infection of RMs elicited high-titer viremia, potent autologous tier 2 neutralizing antibodies, and rapid sequence escape in the canonical V2-apex epitope. Six of seven animals also developed low-titer heterologous plasma breadth that mapped to the V2-apex. Antibody cloning from two of these animals identified multiple expanded lineages with long heavy chain third complementarity determining regions that cross-neutralized as many as 7 of 19 primary HIV-1 strains, but with low potency. Negative stain electron microscopy (NSEM) of members of the two most cross-reactive lineages confirmed V2 targeting but identified an angle of approach distinct from prototypical V2-apex bNAbs, with antibody binding either requiring or inducing an occluded-open trimer. Probing with conformation-sensitive, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency. |
format | Online Article Text |
id | pubmed-9973348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-99733482023-03-01 A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies Bibollet-Ruche, Frederic Russell, Ronnie M. Ding, Wenge Liu, Weimin Li, Yingying Wagh, Kshitij Wrapp, Daniel Habib, Rumi Skelly, Ashwin N. Roark, Ryan S. Sherrill-Mix, Scott Wang, Shuyi Rando, Juliette Lindemuth, Emily Cruickshank, Kendra Park, Younghoon Baum, Rachel Carey, John W. Connell, Andrew Jesse Li, Hui Giorgi, Elena E. Song, Ge S. Ding, Shilei Finzi, Andrés Newman, Amanda Hernandez, Giovanna E. Machiele, Emily Cain, Derek W. Mansouri, Katayoun Lewis, Mark G. Montefiori, David C. Wiehe, Kevin J. Alam, S. Munir Teng, I-Ting Kwong, Peter D. Andrabi, Raiees Verkoczy, Laurent Burton, Dennis R. Korber, Bette T. Saunders, Kevin O. Haynes, Barton F. Edwards, Robert J. Shaw, George M. Hahn, Beatrice H. mBio Research Article HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germ line-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-expressing knock-in mice and as chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) in rhesus macaques (RMs). Trimer immunization of knock-in mice induced V2-directed NAbs, indicating activation of V2-apex bNAb precursor-expressing mouse B cells. SCIV infection of RMs elicited high-titer viremia, potent autologous tier 2 neutralizing antibodies, and rapid sequence escape in the canonical V2-apex epitope. Six of seven animals also developed low-titer heterologous plasma breadth that mapped to the V2-apex. Antibody cloning from two of these animals identified multiple expanded lineages with long heavy chain third complementarity determining regions that cross-neutralized as many as 7 of 19 primary HIV-1 strains, but with low potency. Negative stain electron microscopy (NSEM) of members of the two most cross-reactive lineages confirmed V2 targeting but identified an angle of approach distinct from prototypical V2-apex bNAbs, with antibody binding either requiring or inducing an occluded-open trimer. Probing with conformation-sensitive, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency. American Society for Microbiology 2023-01-11 /pmc/articles/PMC9973348/ /pubmed/36629414 http://dx.doi.org/10.1128/mbio.03370-22 Text en Copyright © 2023 Bibollet-Ruche et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Bibollet-Ruche, Frederic Russell, Ronnie M. Ding, Wenge Liu, Weimin Li, Yingying Wagh, Kshitij Wrapp, Daniel Habib, Rumi Skelly, Ashwin N. Roark, Ryan S. Sherrill-Mix, Scott Wang, Shuyi Rando, Juliette Lindemuth, Emily Cruickshank, Kendra Park, Younghoon Baum, Rachel Carey, John W. Connell, Andrew Jesse Li, Hui Giorgi, Elena E. Song, Ge S. Ding, Shilei Finzi, Andrés Newman, Amanda Hernandez, Giovanna E. Machiele, Emily Cain, Derek W. Mansouri, Katayoun Lewis, Mark G. Montefiori, David C. Wiehe, Kevin J. Alam, S. Munir Teng, I-Ting Kwong, Peter D. Andrabi, Raiees Verkoczy, Laurent Burton, Dennis R. Korber, Bette T. Saunders, Kevin O. Haynes, Barton F. Edwards, Robert J. Shaw, George M. Hahn, Beatrice H. A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies |
title | A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies |
title_full | A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies |
title_fullStr | A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies |
title_full_unstemmed | A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies |
title_short | A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies |
title_sort | germline-targeting chimpanzee siv envelope glycoprotein elicits a new class of v2-apex directed cross-neutralizing antibodies |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973348/ https://www.ncbi.nlm.nih.gov/pubmed/36629414 http://dx.doi.org/10.1128/mbio.03370-22 |
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