title: Human anti-V3 HIV-1 monoclonal antibodies encoded by the VH5-51/VL lambda genes define a conserved antigenic structure.
abstract: Preferential usage of immunoglobulin (Ig) genes that encode antibodies (Abs) against various pathogens is rarely observed and the nature of their dominance is unclear in the context of stochastic recombination of Ig genes. The hypothesis that restricted usage of Ig genes predetermines the antibody specificity was tested in this study of 18 human anti-V3 monoclonal Abs (mAbs) generated from unrelated individuals infected with various subtypes of HIV-1, all of which preferentially used pairing of the VH5-51 and VL lambda genes. Crystallographic analysis of five VH5-51/VL lambda-encoded Fabs complexed with various V3 peptides revealed a common three dimensional (3D) shape of the antigen-binding sites primarily determined by the four complementarity determining regions (CDR) for the heavy (H) and light (L) chains: specifically, the H1, H2, L1 and L2 domains. The CDR H3 domain did not contribute to the shape of the binding pocket, as it had different lengths, sequences and conformations for each mAb. The same shape of the binding site was further confirmed by the identical backbone conformation exhibited by V3 peptides in complex with Fabs which fully adapted to the binding pocket and the same key contact residues, mainly germline-encoded in the heavy and light chains of five Fabs. Finally, the VH5-51 anti-V3 mAbs recognized an epitope with an identical 3D structure which is mimicked by a single mimotope recognized by the majority of VH5-51-derived mAbs but not by other V3 mAbs. These data suggest that the identification of preferentially used Ig genes by neutralizing mAbs may define conserved epitopes in the diverse virus envelopes. This will be useful information for designing vaccine immunogen inducing cross-neutralizing Abs.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, United States of America. mirek.gorny@med.nyu.edu
authors.forename: Miroslaw K
authors.initials: MK
authors.lastname: Gorny
authors.forename: Jared
authors.initials: J
authors.lastname: Sampson
authors.forename: Huiguang
authors.initials: H
authors.lastname: Li
authors.forename: Xunqing
authors.initials: X
authors.lastname: Jiang
authors.forename: Maxim
authors.initials: M
authors.lastname: Totrov
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Wang
authors.forename: Constance
authors.initials: C
authors.lastname: Williams
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Neal
authors.forename: Barbara
authors.initials: B
authors.lastname: Volsky
authors.forename: Liuzhe
authors.initials: L
authors.lastname: Li
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
authors.forename: Phillipe
authors.initials: P
authors.lastname: Nyambi
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.forename: Xiang-Peng
authors.initials: XP
authors.lastname: Kong
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry; D057134:Antibodies, Neutralizing / Q000737:chemistry; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000821:virology; D001665:Binding Sites; D022801:Complementarity Determining Regions; D018360:Crystallography, X-Ray / Q000379:methods; D000939:Epitopes / Q000737:chemistry; D015483:HIV Antibodies / Q000737:chemistry*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry*; D007136:Immunoglobulins / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D022801:Complementarity Determining Regions; D000939:Epitopes; D015483:HIV Antibodies; D007128:Immunoglobulin Fragments; D007136:Immunoglobulins; D010455:Peptides