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

Victoria Oakes, Johana Torralba, Edurne Rujas, José L Nieva, Carmen Domene, Beatriz Apellaniz

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1259-1271
Number of pages13
JournalBiochimica et Biophysica Acta
Volume1860
Issue number6
Early online date23 Feb 2018
DOIs
Publication statusPublished - 1 Jun 2018

Keywords

  • AIDS Vaccines
  • Amino Acid Sequence
  • Antibodies, Neutralizing/immunology
  • Antigen-Antibody Reactions
  • Antigens, Surface/chemistry
  • Epitopes/immunology
  • HIV Antibodies/immunology
  • HIV Envelope Protein gp41/chemistry
  • HIV-1/immunology
  • Humans
  • Liposomes
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Peptide Fragments/immunology
  • Protein Conformation
  • Protein Domains

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