Focal accumulation of aromaticity at the CDRH3loop mitigates 4E10 polyreactivity withoutaltering its HIV neutralization profile

in: iScience (2021)
Rujas, Edurne; Leaman, Daniel P.; Insausti, Sara; Carravilla, Pablo; García-Porras, Miguel; Largo, Eneko; Morillo, Izaskun; Sánchez-Eugenia, Rubén; Zhang, Lei; Cui, Hong; Iloro, Ibon; Elortza, Félix; Julien, Jean-Philippe; Eggeling, Christian; Zwick, Michael B.; Caaveiro, Jose M. M.; Nieva, José L.
Broadly neutralizing antibodies (bnAbs) against HIV-1 are frequently associatedwith the presence of autoreactivity/polyreactivity, a property that can limit theiruse as therapeutic agents. The bnAb 4E10, targeting the conserved Membraneproximal external region (MPER) of HIV-1, displays almost pan-neutralizingactivity across globally circulating HIV-1 strains but exhibits nonspecific off-target interactions with lipid membranes. The hydrophobic apex of the thirdcomplementarity-determining region of the heavy chain (CDRH3) loop, which isessential for viral neutralization, critically contributes to this detrimental effect.Here, we have replaced the aromatic/hydrophobic residues from the apex ofthe CDRH3 of 4E10 with a single aromatic molecule through chemical modifica-tion to generate a variant that preserves the neutralization potency and breadthof 4E10 but with reduced autoreactivity. Collectively, our study suggests thatthe localized accumulation of aromaticity by chemical modification provides apathway to ameliorate the adverse effects triggered by the CDRH3 of anti-HIV-1 MPER bnAbs.

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