Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.

Understanding the molecular mechanisms by which antibodies target and neutralize the HIV-1 envelope glycoprotein (Env) is critical in guiding immunogen design and vaccine development aimed at eliciting cross-reactive neutralizing antibodies (NAbs). Here, we analyzed monoclonal antibodies (mAbs) isol...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Safia S Aljedani, Tyler J Liban, Karen Tran, Ganesh Phad, Suruchi Singh, Viktoriya Dubrovskaya, Pradeepa Pushparaj, Paola Martinez-Murillo, Justas Rodarte, Alex Mileant, Vidya Mangala Prasad, Rachel Kinzelman, Sijy O'Dell, John R Mascola, Kelly K Lee, Gunilla B Karlsson Hedestam, Richard T Wyatt, Marie Pancera
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5d1e169cb38444308637152c824457f6
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5d1e169cb38444308637152c824457f6
record_format	dspace
spelling	oai:doaj.org-article:5d1e169cb38444308637152c824457f62021-12-02T20:00:06ZStructurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.1553-73661553-737410.1371/journal.ppat.1009543https://doaj.org/article/5d1e169cb38444308637152c824457f62021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009543https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Understanding the molecular mechanisms by which antibodies target and neutralize the HIV-1 envelope glycoprotein (Env) is critical in guiding immunogen design and vaccine development aimed at eliciting cross-reactive neutralizing antibodies (NAbs). Here, we analyzed monoclonal antibodies (mAbs) isolated from non-human primates (NHPs) immunized with variants of a native flexibly linked (NFL) HIV-1 Env stabilized trimer derived from the tier 2 clade C 16055 strain. The antibodies displayed neutralizing activity against the autologous virus with potencies ranging from 0.005 to 3.68 μg/ml (IC50). Structural characterization using negative-stain EM and X-ray crystallography identified the variable region 2 (V2) of the 16055 NFL trimer to be the common epitope for these antibodies. The crystal structures revealed that the V2 segment adopts a β-hairpin motif identical to that observed in the 16055 NFL crystal structure. These results depict how vaccine-induced antibodies derived from different clonal lineages penetrate through the glycan shield to recognize a hypervariable region within V2 (residues 184-186) that is unique to the 16055 strain. They also provide potential explanations for the potent autologous neutralization of these antibodies, confirming the immunodominance of this site and revealing that multiple angles of approach are permissible for affinity/avidity that results in potent neutralizing capacity. The structural analysis reveals that the most negatively charged paratope correlated with the potency of the mAbs. The atomic level information is of interest to both define the means of autologous neutralization elicited by different tier 2-based immunogens and facilitate trimer redesign to better target more conserved regions of V2 to potentially elicit cross-neutralizing HIV-1 antibodies.Safia S AljedaniTyler J LibanKaren TranGanesh PhadSuruchi SinghViktoriya DubrovskayaPradeepa PushparajPaola Martinez-MurilloJustas RodarteAlex MileantVidya Mangala PrasadRachel KinzelmanSijy O'DellJohn R MascolaKelly K LeeGunilla B Karlsson HedestamRichard T WyattMarie PanceraPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 9, p e1009543 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Safia S Aljedani Tyler J Liban Karen Tran Ganesh Phad Suruchi Singh Viktoriya Dubrovskaya Pradeepa Pushparaj Paola Martinez-Murillo Justas Rodarte Alex Mileant Vidya Mangala Prasad Rachel Kinzelman Sijy O'Dell John R Mascola Kelly K Lee Gunilla B Karlsson Hedestam Richard T Wyatt Marie Pancera Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.
description	Understanding the molecular mechanisms by which antibodies target and neutralize the HIV-1 envelope glycoprotein (Env) is critical in guiding immunogen design and vaccine development aimed at eliciting cross-reactive neutralizing antibodies (NAbs). Here, we analyzed monoclonal antibodies (mAbs) isolated from non-human primates (NHPs) immunized with variants of a native flexibly linked (NFL) HIV-1 Env stabilized trimer derived from the tier 2 clade C 16055 strain. The antibodies displayed neutralizing activity against the autologous virus with potencies ranging from 0.005 to 3.68 μg/ml (IC50). Structural characterization using negative-stain EM and X-ray crystallography identified the variable region 2 (V2) of the 16055 NFL trimer to be the common epitope for these antibodies. The crystal structures revealed that the V2 segment adopts a β-hairpin motif identical to that observed in the 16055 NFL crystal structure. These results depict how vaccine-induced antibodies derived from different clonal lineages penetrate through the glycan shield to recognize a hypervariable region within V2 (residues 184-186) that is unique to the 16055 strain. They also provide potential explanations for the potent autologous neutralization of these antibodies, confirming the immunodominance of this site and revealing that multiple angles of approach are permissible for affinity/avidity that results in potent neutralizing capacity. The structural analysis reveals that the most negatively charged paratope correlated with the potency of the mAbs. The atomic level information is of interest to both define the means of autologous neutralization elicited by different tier 2-based immunogens and facilitate trimer redesign to better target more conserved regions of V2 to potentially elicit cross-neutralizing HIV-1 antibodies.
format	article
author	Safia S Aljedani Tyler J Liban Karen Tran Ganesh Phad Suruchi Singh Viktoriya Dubrovskaya Pradeepa Pushparaj Paola Martinez-Murillo Justas Rodarte Alex Mileant Vidya Mangala Prasad Rachel Kinzelman Sijy O'Dell John R Mascola Kelly K Lee Gunilla B Karlsson Hedestam Richard T Wyatt Marie Pancera
author_facet	Safia S Aljedani Tyler J Liban Karen Tran Ganesh Phad Suruchi Singh Viktoriya Dubrovskaya Pradeepa Pushparaj Paola Martinez-Murillo Justas Rodarte Alex Mileant Vidya Mangala Prasad Rachel Kinzelman Sijy O'Dell John R Mascola Kelly K Lee Gunilla B Karlsson Hedestam Richard T Wyatt Marie Pancera
author_sort	Safia S Aljedani
title	Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.
title_short	Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.
title_full	Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.
title_fullStr	Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.
title_full_unstemmed	Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.
title_sort	structurally related but genetically unrelated antibody lineages converge on an immunodominant hiv-1 env neutralizing determinant following trimer immunization.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/5d1e169cb38444308637152c824457f6
work_keys_str_mv	AT safiasaljedani structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT tylerjliban structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT karentran structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT ganeshphad structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT suruchisingh structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT viktoriyadubrovskaya structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT pradeepapushparaj structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT paolamartinezmurillo structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT justasrodarte structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT alexmileant structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT vidyamangalaprasad structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT rachelkinzelman structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT sijyodell structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT johnrmascola structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT kellyklee structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT gunillabkarlssonhedestam structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT richardtwyatt structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization AT mariepancera structurallyrelatedbutgeneticallyunrelatedantibodylineagesconvergeonanimmunodominanthiv1envneutralizingdeterminantfollowingtrimerimmunization
_version_	1718375723436081152

Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.

Ejemplares similares