title: Epitope mapping of broadly neutralizing HIV-2 human monoclonal antibodies.
abstract: Recent studies have shown that natural infection by HIV-2 leads to the elicitation of high titers of broadly neutralizing antibodies (NAbs) against primary HIV-2 strains (T. I. de Silva, et al., J. Virol. 86:930-946, 2012; R. Kong, et al., J. Virol. 86:947-960, 2012; G. Ozkaya Sahin, et al., J. Virol. 86:961-971, 2012). Here, we describe the envelope (Env) binding and neutralization properties of 15 anti-HIV-2 human monoclonal antibodies (MAbs), 14 of which were newly generated from 9 chronically infected subjects. All 15 MAbs bound specifically to HIV-2 gp120 monomers and neutralized heterologous primary virus strains HIV-2(7312A) and HIV-2(ST). Ten of 15 MAbs neutralized a third heterologous primary virus strain, HIV-2(UC1). The median 50% inhibitory concentrations (IC(50)s) for these MAbs were surprisingly low, ranging from 0.007 to 0.028 μg/ml. Competitive Env binding studies revealed three MAb competition groups: CG-I, CG-II, and CG-III. Using peptide scanning, site-directed mutagenesis, chimeric Env constructions, and single-cycle virus neutralization assays, we mapped the epitope of CG-I antibodies to a linear region in variable loop 3 (V3), the epitope of CG-II antibodies to a conformational region centered on the carboxy terminus of V4, and the epitope(s) of CG-III antibodies to conformational regions associated with CD4- and coreceptor-binding sites. HIV-2 Env is thus highly immunogenic in vivo and elicits antibodies having diverse epitope specificities, high potency, and wide breadth. In contrast to the HIV-1 Env trimer, which is generally well shielded from antibody binding and neutralization, HIV-2 is surprisingly vulnerable to broadly reactive NAbs. The availability of 15 human MAbs targeting diverse HIV-2 Env epitopes can facilitate comparative studies of HIV/SIV Env structure, function, antigenicity, and immunogenicity.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kong
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Ivelin
authors.initials: I
authors.lastname: Georgiev
authors.forename: Anita
authors.initials: A
authors.lastname: Changela
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Rowland-Jones
authors.forename: Assan
authors.initials: A
authors.lastname: Jaye
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Guan
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
authors.forename: Johannes P M
authors.initials: JP
authors.lastname: Langedijk
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D057134:Antibodies, Neutralizing / Q000276:immunology; D019921:Biotinylation; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018604:Epitope Mapping / Q000379:methods*; D000939:Epitopes / Q000737:chemistry; D015483:HIV Antibodies / Q000276:immunology; D015658:HIV Infections / Q000276:immunology; D015498:HIV-2 / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009500:Neutralization Tests / Q000379:methods; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D010455:Peptides