title: Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41.
abstract: The identification and epitope mapping of broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibodies (Abs) is important for vaccine design, but, despite much effort, very few such Abs have been forthcoming. Only one broadly neutralizing anti-gp41 monoclonal Ab (MAb), 2F5, has been described. Here we report on two MAbs that recognize a region immediately C-terminal of the 2F5 epitope. Both MAbs were generated from HIV-1-seropositive donors, one (Z13) from an antibody phage display library, and one (4E10) as a hybridoma. Both MAbs recognize a predominantly linear and relatively conserved epitope, compete with each other for binding to synthetic peptide derived from gp41, and bind to HIV-1(MN) virions. By flow cytometry, these MAbs appear to bind relatively weakly to infected cells and this binding is not perturbed by pretreatment of the infected cells with soluble CD4. Despite the apparent linear nature of the epitopes of Z13 and 4E10, denaturation of recombinant envelope protein reduces the binding of these MAbs, suggesting some conformational requirements for full epitope expression. Most significantly, Z13 and 4E10 are able to neutralize selected primary isolates from diverse subtypes of HIV-1 (e.g., subtypes B, C, and E). The results suggest that a rather extensive region of gp41 close to the transmembrane domain is accessible to neutralizing Abs and could form a useful target for vaccine design.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Zwick
authors.forename: A F
authors.initials: AF
authors.lastname: Labrijn
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Spenlehauer
authors.forename: E O
authors.initials: EO
authors.lastname: Saphire
authors.forename: J M
authors.initials: JM
authors.lastname: Binley
authors.forename: J P
authors.initials: JP
authors.lastname: Moore
authors.forename: G
authors.initials: G
authors.lastname: Stiegler
authors.forename: H
authors.initials: H
authors.lastname: Katinger
authors.forename: D R
authors.initials: DR
authors.lastname: Burton
authors.forename: P W
authors.initials: PW
authors.lastname: Parren
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005434:Flow Cytometry; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009500:Neutralization Tests
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41