Recognition and blocking of HIV-1 gp41 pre-transmembrane sequence by monoclonal 4E10 antibody in a raft-like membrane environment

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Abstract

The conserved 664DKWASLWNWFNITNWLWYIK683 (preTM) sequence preceding the transmembrane anchor of human immunodeficiency virus (HIV-1) gp41 glycoprotein subunit is accessible to the broadly neutralizing 4E10 antibody and, therefore, constitutes a potential target for vaccine design. Recently reported structural data are compatible with preTM insertion into the viral external membrane monolayer in the gp41 pre-fusion state (Zhu, P., Liu, J., Bess, J., Chertova, E., Lifson, J. D., Grisé, H., Ofek, G. A., Taylor, K. A., and Roux, K. H. (2006) Nature 441, 847-852). Here we demonstrate that the broadly neutralizing 4E10 antibody is able to specifically block the membrane-restructuring activity of a peptide mimic inserted into membranes. Recognition and restructuring blocking occurred in the presence of cholesterol, whereas transmembrane versions as those promoted in 1-palmitoyl-2- oleoylphosphatidylcholine:sphingomyelin mixtures could not be effectively arrested. Spectrofluorimetric assays using rhodamine-labeled peptides revealed that recognition correlated better with pore-formation blocking than with membrane-fusion inhibition. The capacity of the antibody to recognize preTM peptides in a raft-like environment was further corroborated employing planar-supported lipid layers and fluorescence microscopy. These data support that membrane-bound epitope recognition by 4E10 results in clustering reorganization of preTM at the membrane interface. We propose that this process might interfere with the formation of fusion-competent complexes at the low spike densities existing in the HIV-1 membrane. This work comprises the first experimental report on a lipid-modulated antibody capacity to bind a membrane-bound epitope sequence and arrest its restructuring activity. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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Lorizate, M., Cruz, A., Huarte, N., Kunert, R., Pérez-Gil, J., & Nieva, J. L. (2006). Recognition and blocking of HIV-1 gp41 pre-transmembrane sequence by monoclonal 4E10 antibody in a raft-like membrane environment. Journal of Biological Chemistry, 281(51), 39598–39606. https://doi.org/10.1074/jbc.M605998200

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