Cargando…

HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design

BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4...

Descripción completa

Detalles Bibliográficos
Autores principales: Dam, Kim-Marie A., Barnes, Christopher O., Gristick, Harry B., Schoofs, Till, Gnanapragasam, Priyanthi N. P., Nussenzweig, Michel C., Bjorkman, Pamela J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9576718/
https://www.ncbi.nlm.nih.gov/pubmed/36253376
http://dx.doi.org/10.1038/s41467-022-33860-2
_version_ 1784811594679582720
author Dam, Kim-Marie A.
Barnes, Christopher O.
Gristick, Harry B.
Schoofs, Till
Gnanapragasam, Priyanthi N. P.
Nussenzweig, Michel C.
Bjorkman, Pamela J.
author_facet Dam, Kim-Marie A.
Barnes, Christopher O.
Gristick, Harry B.
Schoofs, Till
Gnanapragasam, Priyanthi N. P.
Nussenzweig, Michel C.
Bjorkman, Pamela J.
author_sort Dam, Kim-Marie A.
collection PubMed
description BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4.1 Å and 3.4 Å single-particle cryo-EM structures of two inferred germline (iGL) BG24 precursors complexed with engineered Env-based immunogens lacking CD4bs N-glycans. Structures reveal critical Env contacts by BG24(iGL) and identify antibody light chain structural features that impede Env recognition. In addition, biochemical data and cryo-EM structures of BG24(iGL) variants bound to Envs with CD4bs glycans present provide insights into N-glycan accommodation, including structural modes of light chain adaptations in the presence of the N276(gp120) glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design.
format Online
Article
Text
id pubmed-9576718
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-95767182022-10-19 HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design Dam, Kim-Marie A. Barnes, Christopher O. Gristick, Harry B. Schoofs, Till Gnanapragasam, Priyanthi N. P. Nussenzweig, Michel C. Bjorkman, Pamela J. Nat Commun Article BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4.1 Å and 3.4 Å single-particle cryo-EM structures of two inferred germline (iGL) BG24 precursors complexed with engineered Env-based immunogens lacking CD4bs N-glycans. Structures reveal critical Env contacts by BG24(iGL) and identify antibody light chain structural features that impede Env recognition. In addition, biochemical data and cryo-EM structures of BG24(iGL) variants bound to Envs with CD4bs glycans present provide insights into N-glycan accommodation, including structural modes of light chain adaptations in the presence of the N276(gp120) glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design. Nature Publishing Group UK 2022-10-17 /pmc/articles/PMC9576718/ /pubmed/36253376 http://dx.doi.org/10.1038/s41467-022-33860-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Dam, Kim-Marie A.
Barnes, Christopher O.
Gristick, Harry B.
Schoofs, Till
Gnanapragasam, Priyanthi N. P.
Nussenzweig, Michel C.
Bjorkman, Pamela J.
HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design
title HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design
title_full HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design
title_fullStr HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design
title_full_unstemmed HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design
title_short HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design
title_sort hiv-1 cd4-binding site germline antibody–env structures inform vaccine design
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9576718/
https://www.ncbi.nlm.nih.gov/pubmed/36253376
http://dx.doi.org/10.1038/s41467-022-33860-2
work_keys_str_mv AT damkimmariea hiv1cd4bindingsitegermlineantibodyenvstructuresinformvaccinedesign
AT barneschristophero hiv1cd4bindingsitegermlineantibodyenvstructuresinformvaccinedesign
AT gristickharryb hiv1cd4bindingsitegermlineantibodyenvstructuresinformvaccinedesign
AT schoofstill hiv1cd4bindingsitegermlineantibodyenvstructuresinformvaccinedesign
AT gnanapragasampriyanthinp hiv1cd4bindingsitegermlineantibodyenvstructuresinformvaccinedesign
AT nussenzweigmichelc hiv1cd4bindingsitegermlineantibodyenvstructuresinformvaccinedesign
AT bjorkmanpamelaj hiv1cd4bindingsitegermlineantibodyenvstructuresinformvaccinedesign