title: Role of HIV membrane in neutralization by two broadly neutralizing antibodies.
abstract: Induction of effective antibody responses against HIV-1 infection remains an elusive goal for vaccine development. Progress may require in-depth understanding of the molecular mechanisms of neutralization by monoclonal antibodies. We have analyzed the molecular actions of two rare, broadly neutralizing, human monoclonal antibodies, 4E10 and 2F5, which target the transiently exposed epitopes in the membrane proximal external region (MPER) of HIV-1 gp41 envelope during viral entry. Both have long CDR H3 loops with a hydrophobic surface facing away from the peptide epitope. We find that the hydrophobic residues of 4E10 mediate a reversible attachment to the viral membrane and that they are essential for neutralization, but not for interaction with gp41. We propose that these antibodies associate with the viral membrane in a required first step and are thereby poised to capture the transient gp41 fusion intermediate. These results bear directly on strategies for rational design of HIV-1 envelope immunogens.
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. alam0004@mc.duke.edu
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.forename: Marco
authors.initials: M
authors.lastname: Morelli
authors.forename: S Moses
authors.initials: SM
authors.lastname: Dennison
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.forename: Ruijun
authors.initials: R
authors.lastname: Zhang
authors.forename: Shi-Mao
authors.initials: SM
authors.lastname: Xia
authors.forename: Sophia
authors.initials: S
authors.lastname: Rits-Volloch
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
mesh_terms: D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008567:Membranes, Artificial; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009500:Neutralization Tests; D011485:Protein Binding / Q000235:genetics; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015700:HIV Envelope Protein gp41; D008567:Membranes, Artificial; D014765:Viral Vaccines