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.

 Descargar el artículo 

¿Acabas de publicar un artículo interesante?

Manda la referencia a través de nuestro formulario.  Límite de edad 32 años. Los artículos seleccionados serán destacados como artículos del mes y participarán en el Premio al mejor artículo de jóvenes de la SEBBM, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

A Mammalian Target of Rapamycin-Perilipin 3 (mTORC1-Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis

24-09-2021

Background and Aims: NAFLD is the most common hepatic pathology in western countries and no treatment is currently available. NAFLD is characterized by the aberrant hepatocellular accumulation of fatty acids...

Leer más

NF-κB/IKK activation by small extracellular vesicles within the SASP

07-09-2021

Cellular senescence plays an important role in different biological and pathological conditions. Senescent cells communicate with their microenvironment through a plethora of soluble factors, metalloproteases and extracellular vesicles (EV). Although...

Leer más

α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity

28-07-2021

α-Synuclein aggregation is a key driver of neurodegeneration in Parkinson's disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein toxic assemblies with high affinity is a long-pursued objective...

Leer más

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism

30-06-2021

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains...

Leer más

G6PD overexpression protects from oxidative stress and age-related hearing loss

23-05-2021

Aging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises...

Leer más

Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

25-04-2021

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO)...

Leer más

Astrocyte-mediated switch in spike timing-dependent plasticity during hippocampal development

29-03-2021

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found...

Leer más

Ceramide chain length–dependent protein sorting into selective endoplasmic reticulum exit sites

22-02-2021

Protein sorting in the secretory pathway is crucial to maintain cellular compartmentalization and homeostasis. In addition to coat-mediated sorting, the role of lipids in driving protein sorting during secretory transport...

Leer más

Antigen retrieval and clearing for whole-organ immunofluorescence by FLASH

25-01-2021

Advances in light-sheet and confocal microscopy now allow imaging of cleared large biological tissue samples and enable the 3D appreciation of cell and protein localization in their native organ environment...

Leer más

Viral Bcl2s' transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis

08-01-2021

Viral control of programmed cell death relies in part on the expression of viral analogs of the B-cell lymphoma 2 (Bcl2) protein known as viral Bcl2s (vBcl2s). vBcl2s control apoptosis...

Leer más

Socios Protectores