title: Identification and characterization of a broadly cross-reactive HIV-1 human monoclonal antibody that binds to both gp120 and gp41.
abstract: Identification of broadly cross-reactive HIV-1-neutralizing antibodies (bnAbs) may assist vaccine immunogen design. Here we report a novel human monoclonal antibody (mAb), designated m43, which co-targets the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein (Env). M43 bound to recombinant gp140 s from various primary isolates, to membrane-associated Envs on transfected cells and HIV-1 infected cells, as well as to recombinant gp120 s and gp41 fusion intermediate structures containing N-trimer structure, but did not bind to denatured recombinant gp140 s and the CD4 binding site (CD4bs) mutant, gp120 D368R, suggesting that the m43 epitope is conformational and overlaps the CD4bs on gp120 and the N-trimer structure on gp41. M43 neutralized 34% of the HIV-1 primary isolates from different clades and all the SHIVs tested in assays based on infection of peripheral blood mononuclear cells (PBMCs) by replication-competent virus, but was less potent in cell line-based pseudovirus assays. In contrast to CD4, m43 did not induce Env conformational changes upon binding leading to exposure of the coreceptor binding site, enhanced binding of mAbs 2F5 and 4E10 specific for the membrane proximal external region (MPER) of gp41 Envs, or increased gp120 shedding. The overall modest neutralization activity of m43 is likely due to the limited binding of m43 to functional Envs which could be increased by antibody engineering if needed. M43 may represent a new class of bnAbs targeting conformational epitopes overlapping structures on both gp120 and gp41. Its novel epitope and possibly new mechanism(s) of neutralization could helpdesign improved vaccine immunogens and candidate therapeutics.
authors.affiliation: AIDS Institute; Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. zhangmy@hku.hk
authors.forename: Mei-Yun
authors.initials: MY
authors.lastname: Zhang
authors.forename: Tingting
authors.initials: T
authors.lastname: Yuan
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosa Borges
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Watkins
authors.forename: Javier
authors.initials: J
authors.lastname: Guenaga
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Wilson
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Polonis
authors.forename: Seth H
authors.initials: SH
authors.lastname: Pincus
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Ruprecht
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D003429:Cross Reactions / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011485:Protein Binding / Q000276:immunology; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000378:metabolism; D017201:Virus Shedding / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D054299:env Gene Products, Human Immunodeficiency Virus