Isotype modulates epitope specificity, affinity, and antiviral activities of anti-HIV-1 human broadly neutralizing 2F5 antibody.
The constant heavy chain (CH1) domain affects antibody affinity and fine specificity, challenging the paradigm that only variable regions contribute to antigen binding. To investigate the role of the CH1 domain, we constructed IgA2 from the broadly neutralizing anti-HIV-1 2F5 IgG1, and compared 2F5 IgA2 and IgG binding affinity and functional activities. We found that 2F5 IgA2 bound to the gp41 membrane proximal external region with higher affinity than IgG1. Functionally, compared with IgG1, 2F5 IgA2 more efficiently blocked HIV-1 transcytosis across epithelial cells and CD4(+) cell infection by R5 HIV-1. The 2F5 IgG1 and IgA2 acted synergistically to fully block HIV-1 transfer from Langerhans to autologous CD4(+) T cells and to inhibit CD4(+) T-cell infection. Epitope mapping performed by screening a random peptide library and in silico docking modeling suggested that along with the 2F5 IgG canonical ELDKWA epitope on gp41, the IgG1 recognized an additional 3D-conformational epitope on the gp41 C-helix. In contrast, the IgA2 epitope included a unique conformational motif on the gp41 N-helix. Overall, the CH1 region of 2F5 contributes to shape its epitope specificity, antibody affinity, and functional activities. In the context of sexually transmitted infections such as HIV-1/AIDS, raising a mucosal IgA-based vaccine response should complement an IgG-based vaccine response in blocking HIV-1 transmission.
Mucosal Entry of HIV-1 and Mucosal Immunity, Cell Biology and Host-Pathogen Interactions Department, Cochin Institute, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, 75014 Paris, France.
Daniela
D
Tudor
Huifeng
H
Yu
Julien
J
Maupetit
Anne-Sophie
AS
Drillet
Tahar
T
Bouceba
Isabelle
I
Schwartz-Cornil
Lucia
L
Lopalco
Pierre
P
Tuffery
Morgane
M
Bomsel
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000628:therapy / Q000635:transmission; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D000918:Antibody Specificity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D057900:Transcytosis / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D007074:Immunoglobulin G; C514787:gp41 protein, Human immunodeficiency virus 1