Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile.
immunology
virology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
24 Sep 2021
24 Sep 2021
Historique:
received:
14
04
2021
revised:
08
07
2021
accepted:
12
08
2021
entrez:
10
9
2021
pubmed:
11
9
2021
medline:
11
9
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34505005
doi: 10.1016/j.isci.2021.102987
pii: S2589-0042(21)00955-X
pmc: PMC8413895
doi:
Types de publication
Journal Article
Langues
eng
Pagination
102987Subventions
Organisme : NIAID NIH HHS
ID : R01 AI143563
Pays : United States
Informations de copyright
© 2021 The Author(s).
Déclaration de conflit d'intérêts
A patent application covering several aspects of this work has been filled by Kyushu University/UPV-EHU/CSIC/FBB, listing E.R., R.S.-E., J.L.N., and J.M.M.C. as inventors. All other authors declare no competing interests.
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