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dc.contributor.authorFriedrich, Nikolas
dc.contributor.authorStiegeler, Emanuel
dc.contributor.authorGlögl, Matthias
dc.contributor.authorLemmin, Thomas
dc.contributor.authorHansen, Simon
dc.contributor.authorKadelka, Claus
dc.contributor.authorWu, Yufan
dc.contributor.authorErnst, Patrick
dc.contributor.authorMaliqi, Liridona
dc.contributor.authorFoulkes, Caio
dc.contributor.authorMorin, Mylène
dc.contributor.authorEroglu, Mustafa
dc.contributor.authorLiechti, Thomas
dc.contributor.authorIvan, Branislav
dc.contributor.authorReinberg, Thomas
dc.contributor.authorSchaefer, Jonas V
dc.contributor.authorKarakus, Umut
dc.contributor.authorUrsprung, Stephan
dc.contributor.authorMann, Axel
dc.contributor.authorRusert, Peter
dc.contributor.authorKouyos, Roger D
dc.contributor.authorRobinson, John A
dc.contributor.authorGünthard, Huldrych F
dc.contributor.authorPlückthun, Andreas
dc.contributor.authorTrkola, Alexandra
dc.date.accessioned2022-01-07T16:51:49Z
dc.date.available2022-01-07T16:51:49Z
dc.date.issued2021-11-18
dc.identifier.issn2041-1723
dc.identifier.otherPMC8602657
dc.identifier.other34795280
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332402
dc.description.abstractThe V3 loop of the HIV-1 envelope (Env) protein elicits a vigorous, but largely non-neutralizing antibody response directed to the V3-crown, whereas rare broadly neutralizing antibodies (bnAbs) target the V3-base. Challenging this view, we present V3-crown directed broadly neutralizing Designed Ankyrin Repeat Proteins (bnDs) matching the breadth of V3-base bnAbs. While most bnAbs target prefusion Env, V3-crown bnDs bind open Env conformations triggered by CD4 engagement. BnDs achieve breadth by focusing on highly conserved residues that are accessible in two distinct V3 conformations, one of which resembles CCR5-bound V3. We further show that these V3-crown conformations can, in principle, be attacked by antibodies. Supporting this conclusion, analysis of antibody binding activity in the Swiss 4.5 K HIV-1 cohort (n = 4,281) revealed a co-evolution of V3-crown reactivities and neutralization breadth. Our results indicate a role of V3-crown responses and its conformational preferences in bnAb development to be considered in preventive and therapeutic approaches.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 2041-1723
dc.sourcenlmid: 101528555
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectHIV-1
dc.subjectImmunoglobulin G
dc.subjectHIV Antibodies
dc.subjectEpitopes
dc.subjectProtein Conformation
dc.subjectProtein Binding
dc.subjectMutation
dc.subjectenv Gene Products, Human Immunodeficiency Virus
dc.subjectMolecular Dynamics Simulation
dc.subjectAntibodies, Neutralizing
dc.subjectHEK293 Cells
dc.subjectMolecular Docking Simulation
dc.titleDistinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization.
dc.typeArticle
dc.date.updated2022-01-07T16:51:49Z
prism.issueIdentifier1
prism.publicationNameNat Commun
prism.volume12
dc.identifier.doi10.17863/CAM.79848
dcterms.dateAccepted2021-11-03
rioxxterms.versionofrecord10.1038/s41467-021-27075-0
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidFriedrich, Nikolas [0000-0003-0694-657X]
dc.contributor.orcidKadelka, Claus [0000-0002-5712-8529]
dc.contributor.orcidErnst, Patrick [0000-0001-6037-1856]
dc.contributor.orcidUrsprung, Stephan [0000-0003-2476-178X]
dc.contributor.orcidKouyos, Roger D [0000-0002-9220-8348]
dc.contributor.orcidRobinson, John A [0000-0001-7857-8556]
dc.contributor.orcidGünthard, Huldrych F [0000-0002-1142-6723]
dc.contributor.orcidPlückthun, Andreas [0000-0003-4191-5306]
dc.contributor.orcidTrkola, Alexandra [0000-0003-1013-876X]
dc.identifier.eissn2041-1723
pubs.funder-project-idSwiss National Science Foundation (166676, 152663, 190705, 310030, 172790, 192689, 179571, 314730, 142411, 155851, 148522)
cam.issuedOnline2021-11-18


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International