Structure and Immunogenicity of a Peptide Vaccine, Including the Complete HIV-1 gp41 2F5 Epitope: IMPLICATIONS FOR ANTIBODY RECOGNITION MECHANISM AND IMMUNOGEN DESIGN

Soraya Serrano, Aitziber Araujo, Beatriz Apellaniz, Steve Bryson, Pablo Carravilla, Igor de la Arada, Nerea Huarte, Edurne Rujas, Emil F. Pai, Jose L. R. Arrondo, Carmen Domene Nunez, Maria Angeles Jimenez, Jose L. Nieva

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

The membrane-proximal external region (MPER) of gp41 harbors the epitope recognized by the broadly neutralizing anti-HIV 2F5 antibody, a research focus in HIV-1 vaccine development. In this work, we analyze the structure and immunogenic properties of MPERp, a peptide vaccine that includes the following: (i) the complete sequence protected from proteolysis by the 2F5 paratope; (ii) downstream residues postulated to establish weak contacts with the CDR-H3 loop of the antibody, which are believed to be crucial for neutralization; and (iii) an aromatic rich anchor to the membrane interface. MPERp structures solved in dodecylphosphocholine micelles and 25% 1,1,1,3,3,3-hexafluoro-2-propanol (v/v) confirmed folding of the complete 2F5 epitope within continuous kinked helices. Infrared spectroscopy (IR) measurements demonstrated the retention of main helical conformations in immunogenic formulations based on alum, Freund's adjuvant, or two different types of liposomes. Binding to membrane-inserted MPERp, IR, molecular dynamics simulations, and characterization of the immune responses further suggested that packed helical bundles partially inserted into the lipid bilayer, rather than monomeric helices adsorbed to the membrane interface, could encompass effective MPER peptide vaccines. Together, our data constitute a proof-of-concept to support MPER-based peptides in combination with liposomes as stand-alone immunogens and suggest new approaches for structure-aided MPER vaccine development.
Original languageEnglish
Pages (from-to)6565-6580
Number of pages16
JournalJournal of Biological Chemistry
Volume289
Issue number10
DOIs
Publication statusPublished - 1 Mar 2014

Keywords

  • Fourier Transform IR (FTIR), HIV-1, Liposomes, Nuclear Magnetic Resonance, Peptide Conformation, Vaccine Development, IMMUNODEFICIENCY-VIRUS TYPE-1, PROXIMAL EXTERNAL REGION, HUMAN MONOCLONAL-ANTIBODY, BROADLY NEUTRALIZING ANTIBODIES, ENVELOPE GLYCOPROTEIN, MOLECULAR-DYNAMICS, MEDIATED FUSION, NMR STRUCTURE, FORCE-FIELD, MEMBRANE

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