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Biochim Biophys Acta Biomembr. 2018 Jun;1860(6):1259-1271. doi: 10.1016/j.bbamem.2018.02.019. Epub 2018 Feb 23.

Exposure of the HIV-1 broadly neutralizing antibody 10E8 MPER epitope on the membrane surface by gp41 transmembrane domain scaffolds.

Author information

1
Department of Chemistry, Britannia House, 7 Trinity Street, King's College London, London SE1 1DB, UK; Department of Chemistry, 1 South Building, Claverton Down Road, University of Bath, Bath BA2 7AY, UK.
2
Biofisika Institute (CSIC, UPV/EHU), Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), PO Box 644, 48080 Bilbao, Spain.
3
Department of Chemistry, 1 South Building, Claverton Down Road, University of Bath, Bath BA2 7AY, UK; Chemistry Research Laboratory, Mansfield Road, University of Oxford, Oxford OX1 3TA, UK. Electronic address: C.Domene@bath.ac.uk.
4
Biofisika Institute (CSIC, UPV/EHU), Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), PO Box 644, 48080 Bilbao, Spain. Electronic address: beatriz.apellaniz@ehu.eus.

Abstract

The 10E8 antibody achieves near-pan neutralization of HIV-1 by targeting the remarkably conserved gp41 membrane-proximal external region (MPER) and the connected transmembrane domain (TMD) of the HIV-1 envelope glycoprotein (Env). Thus, recreating the structure that generates 10E8-like antibodies is a major goal of the rational design of anti-HIV vaccines. Unfortunately, high-resolution information of this segment in the native Env is lacking, limiting our understanding of the behavior of the crucial 10E8 epitope residues. In this report, two sequences, namely, MPER-TMD1 (gp41 residues 671-700) and MPER-TMD2 (gp41 residues 671-709) were compared both experimentally and computationally, to assess the TMD as a potential membrane integral scaffold for the 10E8 epitope. These sequences were selected to represent a minimal (MPER-TMD1) or full-length (MPER-TMD2) TMD membrane anchor according to mutagenesis results reported by Yue et al. (2009) J. Virol. 83, 11,588. Immunochemical assays revealed that MPER-TMD1, but not MPER-TMD2, effectively exposed the MPER C-terminal stretch, harboring the 10E8 epitope on the surface of phospholipid bilayers containing a cholesterol concentration equivalent to that of the viral envelope. Molecular dynamics simulations, using the recently resolved TMD trimer structure combined with the MPER in a cholesterol-enriched model membrane confirmed these results and provided an atomistic mechanism of epitope exposure which revealed that TMD truncation at position A700 combined with N-terminal addition of lysine residues positively impacts epitope exposure. Overall, these results provide crucial insights into the design of effective MPER-TMD derived immunogens.

KEYWORDS:

Antigenicity; HIV-1; Molecular dynamics simulation; Transmembrane domain; Vaccine development

PMID:
29477358
DOI:
10.1016/j.bbamem.2018.02.019
[Indexed for MEDLINE]

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