Identification and characterization of a broadly cross-reactive HIV-1 human monoclonal antibody that binds to both gp120 and gp41.

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleIdentification and characterization of a broadly cross-reactive HIV-1 human monoclonal antibody that binds to both gp120 and gp41.
Publication TypeJournal Article
Year of Publication2012
AuthorsZhang, M-Y, Yuan, T, Li, J, Borges, ARosa, Watkins, JD, Guenaga, J, Yang, Z, Wang, Y, Wilson, R, Li, Y, Polonis, VR, Pincus, SH, Ruprecht, RM, Dimitrov, DS
JournalPLoS One
Date Published2012
KeywordsAmino Acid Sequence, Antibodies, Monoclonal, Antibodies, Neutralizing, Antigens, CD4, Cross Reactions, env Gene Products, Human Immunodeficiency Virus, Epitopes, Flow Cytometry, HIV Envelope Protein gp120, HIV Envelope Protein gp41, HIV-1, Humans, Immunoglobulin Fab Fragments, Immunoglobulin G, Molecular Sequence Data, Neutralization Tests, Protein Binding, Protein Multimerization, Recombinant Proteins, Virus Shedding

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.

Alternate JournalPLoS ONE
PubMed ID22970187
PubMed Central IDPMC3438192
Grant ListAND P01 AI048240 / AI / NIAID NIH HHS / United States
R37 AI034266 / AI / NIAID NIH HHS / United States