Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile

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...

Descripción completa

Detalles Bibliográficos
Autores: 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, José M. M., Nieva, José Luis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/311050
Acceso en línea:http://hdl.handle.net/10261/311050
https://api.elsevier.com/content/abstract/scopus_id/85122787803
Access Level:acceso abierto
Palabra clave:Immunology
Virology
Descripción
Sumario: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.

Similares en LA Referencia