title: The broadly neutralizing anti-human immunodeficiency virus type 1 4E10 monoclonal antibody is better adapted to membrane-bound epitope recognition and blocking than 2F5.
abstract: The broadly neutralizing 2F5 and 4E10 monoclonal antibodies (MAbs) recognize epitopes within the membrane-proximal external region (MPER) that connects the human immunodeficiency virus type 1 (HIV-1) envelope gp41 ectodomain with the transmembrane anchor. By adopting different conformations that stably insert into the virion external membrane interface, such as helical structures, a conserved aromatic-rich sequence within the MPER is thought to participate in HIV-1-cell fusion. Recent experimental evidence suggests that the neutralizing activity of 2F5 and 4E10 might correlate with the MAbs' capacity to recognize epitopes inserted into the viral membrane, thereby impairing MPER fusogenic activity. To gain new insights into the molecular mechanism underlying viral neutralization by these antibodies, we have compared the capacities of 2F5 and 4E10 to block the membrane-disorganizing activity of MPER peptides inserted into the surface bilayer of solution-diffusing unilamellar vesicles. Both MAbs inhibited leakage of vesicular aqueous contents (membrane permeabilization) and intervesicular lipid mixing (membrane fusion) promoted by MPER-derived peptides. Thus, our data support the idea that antibody binding to a membrane-inserted epitope may interfere with the function of the MPER during gp41-induced fusion. Antibody insertion into a cholesterol-containing, uncharged virion-like membrane is mediated by specific epitope recognition, and moreover, partitioning-coupled folding into a helix reduces the efficiency of 2F5 MAb binding to its epitope in the membrane. We conclude that the capacity to interfere with the membrane activity of conserved MPER sequences is best correlated with the broad neutralization of the 4E10 MAb.
authors.affiliation: Unidad de Biofísica (CSIC-UPV/EHU), Universidad del País Vasco, Aptdo 644, 48080 Bilbao, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Huarte
authors.forename: Maier
authors.initials: M
authors.lastname: Lorizate
authors.forename: Rubén
authors.initials: R
authors.lastname: Maeso
authors.forename: Renate
authors.initials: R
authors.lastname: Kunert
authors.forename: Rocio
authors.initials: R
authors.lastname: Arranz
authors.forename: José M
authors.initials: JM
authors.lastname: Valpuesta
authors.forename: José L
authors.initials: JL
authors.lastname: Nieva
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002463:Cell Membrane Permeability; D000939:Epitopes / Q000276:immunology*; D005434:Flow Cytometry; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008055:Lipids; D008081:Liposomes; D008561:Membrane Fusion; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009500:Neutralization Tests
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D008055:Lipids; D008081:Liposomes