Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile
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Date
2021-09-24Author
Rujas Díez, Edurne
Leaman, Daniel P.
Insausti González, Sara
Carravilla Palomanes, Pablo
García Porras, Miguel
Largo Pereda, Eneko
Morillo Melero, Izaskun
Zhang, Lei
Cui, Hong
Iloro, Ibon
Elortza, Felix
Julien, Jean-Philippe
Eggeling, Christian
Zwick, Michael B.
Caaveiro, Jose M.M.
Nieva Escandón, José Luis
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iScience 24(9) : (2021) // Article ID 102987
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.