dc.contributor.author | Rujas Díez, Edurne | |
dc.contributor.author | Leaman, Daniel P. | |
dc.contributor.author | Insausti González, Sara | |
dc.contributor.author | Carravilla Palomanes, Pablo ![ORCID](/themes/Mirage2//images/orcid_16x16.png) | |
dc.contributor.author | García Porras, Miguel | |
dc.contributor.author | Largo Pereda, Eneko | |
dc.contributor.author | Morillo Melero, Izaskun | |
dc.contributor.author | Sánchez Eugenia, Rubén ![ORCID](/themes/Mirage2//images/orcid_16x16.png) | |
dc.contributor.author | Zhang, Lei | |
dc.contributor.author | Cui, Hong | |
dc.contributor.author | Iloro, Ibon | |
dc.contributor.author | Elortza, Felix | |
dc.contributor.author | Julien, Jean-Philippe | |
dc.contributor.author | Eggeling, Christian | |
dc.contributor.author | Zwick, Michael B. | |
dc.contributor.author | Caaveiro, Jose M.M. | |
dc.contributor.author | Nieva Escandón, José Luis | |
dc.date.accessioned | 2021-10-25T07:39:37Z | |
dc.date.available | 2021-10-25T07:39:37Z | |
dc.date.issued | 2021-09-24 | |
dc.identifier.citation | iScience 24(9) : (2021) // Article ID 102987 | es_ES |
dc.identifier.issn | 2589-0042 | |
dc.identifier.uri | http://hdl.handle.net/10810/53612 | |
dc.description.abstract | Broadly neutralizing antibodies (bnAbs) against HIV-1 are frequently associated with the presence of autoreactivity/polyreactivity, a property that can limit their use as therapeutic agents. The bnAb 4E10, targeting the conserved Membrane proximal external region (MPER) of HIV-1, displays almost pan-neutralizing activity across globally circulating HIV-1 strains but exhibits nonspecific off-target interactions with lipid membranes. The hydrophobic apex of the third complementarity-determining region of the heavy chain (CDRH3) loop, which is essential for viral neutralization, critically contributes to this detrimental effect. Here, we have replaced the aromatic/hydrophobic residues from the apex of the CDRH3 of 4E10 with a single aromatic molecule through chemical modification to generate a variant that preserves the neutralization potency and breadth of 4E10 but with reduced autoreactivity. Collectively, our study suggests that the localized accumulation of aromaticity by chemical modification provides a pathway to ameliorate the adverse effects triggered by the CDRH3 of anti-HIV-1 MPER bnAbs. | es_ES |
dc.description.sponsorship | This study was supported by the following Grants: European Commission (790012 SI H2020-MSCA-IF-2017) (E.R.); US NIAID, NIH grant R01 AI143563 (M.B. Z.); James B. Pendleton Charitable Trust (M.B.Z.); JSPS grant 20H03228 (J. M.M.C.); Spanish MCIU (RTI2018-095624-B-C21; MCIU/AEI/FEDER, UE) (J.L.N.), Basque Government (IT1196-19) (J.L.N.). C.E. acknowledges funding from Medical Research Council (grant number MC_UU_12010/unit programs G0902418 and MC_UU_12025), Wolfson Foundation, Deutsche Forschungsgemeinschaft (Excellence Cluster Balance of the Microverse, Collaborative Research Center 1278 Polytarget), Leibniz Association (Leibniz Campus Infectooptics), Wellcome Institutional Strategic Support Fund, Oxford internal funds (EPA Cephalosporin Fund and John Fell Fund), and support from the Micron Oxford Advanced Bioimaging Unit (Wellcome Trust funding 107457/Z/15/Z). This work was also supported by the Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED (JP21am0101091). S.I. received a predoctoral fellowship from the BasqueGovernment. P.C. would like to acknowledge the University of the Basque Country (DOCREC18/01), the Basque Government (POS_2018_1_0066) and the European Commission (H2020-MSCA-IF-2019-ST project 892232 FILM-HIV) for funding his position. This research was also supported by the CIFAR Azrieli Global Scholar program (J-P.J.), the Ontario Early Researcher Awards program (J-P.J.), and the Canada Research Chairs program (J-P.J.). Part of the biophysical data presented in this manuscript were collected at the Hospital for Sick Children Structural & Biophysical Core facility supported by the Canada Foundation for Innovation and Ontario Research Fund. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Cell Press | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/892232 | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/790012 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/RTI2018-095624-B-C21 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.title | Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 4.0) | es_ES |
dc.rights.holder | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.relation.publisherversion | https://www-sciencedirect-com.ehu.idm.oclc.org/science/article/pii/S258900422100955X?via%3Dihub#! | es_ES |
dc.identifier.doi | 10.1016/j.isci.2021.102987 | |
dc.contributor.funder | European Commission | |
dc.departamentoes | Bioquímica y biología molecular | es_ES |
dc.departamentoes | Inmunología, microbiología y parasitología | es_ES |
dc.departamentoeu | Biokimika eta biologia molekularra | es_ES |
dc.departamentoeu | Immunologia, mikrobiologia eta parasitologia | es_ES |