Referencia

Functional optimization of broadly neutralizing HIV-1 antibody 10E8 by promoting membrane interactions (2018). Rujas E, Leaman DP, Insausti S, Ortigosa-Pascual L, Zhang L, Zwick MB, Nieva JL. J Virol. journalofvirology

Autores

Rujas E, Leaman DP, Insausti S, Ortigosa-Pascual L, Zhang L, Zwick MB, Nieva JL.

Resumen

The 10E8 antibody targets a helical epitope in the membrane-proximal external region (MPER) and transmembrane domain (TMD) of the envelope glycoprotein (Env) subunit gp41 and is among the broadest known neutralizing antibodies against HIV-1. Accordingly, this antibody and its mechanism of action valuably inform the design of effective vaccines and immunotherapies. 10E8 exhibits unusual adaptations to attain specific, high-affinity binding to the MPER at the viral membrane interface. Reversing the charge of the basic paratope surface (from net positive to net negative) reportedly lowered its neutralization potency. Here, we hypothesized that by increasing the net positive charge in similar polar surface patches, the neutralization potency of the antibody may be enhanced. We found that an increased positive charge at this paratope surface strengthened an electrostatic interaction between the antibody and lipid bilayers, enabling 10E8 to interact spontaneously with membranes. Notably, the modified 10E8 antibody did not gain any observable polyreactivity and neutralized virus with a significantly greater potency. Binding analyses indicated that the optimized 10E8 antibody bound with a higher affinity to the epitope peptide anchored in lipid bilayers and to Env spikes on virions. Overall, our data provide a proof of principle for the rational optimization of 10E8 via manipulation of its interaction with the membrane element of its epitope. However, the observation that a similar mutation strategy did not affect the potency of the first-generation anti-MPER antibody 4E10 shows possible limitations of this principle. Altogether, our results emphasize the crucial role played by the viral membrane in the antigenicity of the MPER-TMD of HIV-1.

 

Descripción

El anticuerpo 10E8 representa uno de los anticuerpos anti-VIH con mayor cobertura de neutralización y potencia descrito a día de hoy. Su epítopo se localiza en una región próxima a la membrana y por lo tanto su acceso está parcialmente ocluido por los lípidos. En este trabajo hemos optimizado la superficie del anticuerpo que se aproxima a la membrana tras unirse al epítopo con el objetivo de fortalecer la afinidad del complejo anticuerpo-virus resultando en un anticuerpo entre 10 y 30 veces más potente dependiendo de la cepa de virus usado.

 

 

foto de grupo 2

 

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Jose Luis Nieva presenta una larga trayectoria científica en el estudio de la región denominada MPER del virus del VIH y ha contribuido significativamente a entender el mecanismo por el cual los anticuerpos anti-MPER acceden a sus epítopos parcialmente enterrados dentro de la membrana, un nuevo paradigma que podría tener implicaciones importantes para el diseño de vacunas y / o estudios de inmunoterapia.

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