The CH1α domain of mucosal gp41 IgA contributes to antibody specificity and antiviral functions in HIV-1 highly exposed Sero-Negative individuals.

Antibody Specificity / immunology Binding Sites, Antibody / immunology Epitopes, B-Lymphocyte / chemistry HIV Antibodies / immunology HIV Envelope Protein gp41 / immunology HIV Infections / immunology HIV Seronegativity / immunology HIV-1 / immunology Humans Immunoglobulin A / chemistry Immunoglobulin G / immunology Protein Domains / immunology

Journal

PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921

Informations de publication

Date de publication:
12 2020
Historique:
received: 09 07 2020
accepted: 26 10 2020
revised: 12 01 2021
pubmed: 15 12 2020
medline: 29 1 2021
entrez: 14 12 2020
Statut: epublish

Résumé

The antibody molecule comprises a variable domain conferring antigen specificity and affinity distinct from the heavy chain constant (CH) domains dictating effector functions. We here interrogate this paradigm by evaluating the unique influence of the CH1α domain on epitope specificity and functions using two mucosal gp41-specific Fab-IgAs (FabA) derived from HIV-1 highly-exposed but persistently seronegative individuals (HESN). These HESN develop selectively affinity-matured HIV-1-specific mucosal IgA that target the gp41 viral envelope and might provide protection although by unclear mechanisms. Isotype-switching FabAs into Fab-IgGs (FabGs) results in a >10-fold loss in affinity for HIV-1 clade A, B, and C gp41, together with reduced neutralization of HIV-1 cross-clade. The FabA conformational epitopes map selectively on gp41 in 6-Helix bundle and pre-fusion conformations cross-clade, unlike FabGs. Finally, we designed in silico, a 12 amino-acid peptide recapitulating one FabA conformational epitope that inhibits the FabA binding to gp41 cross-clade and its neutralizing activity. Altogether, our results reveal that the CH1α domain shapes the antibody paratope through an allosteric effect, thereby strengthening the antibody specificity and functional activities. Further, they clarify the mechanisms by which these HESN IgAs might confer protection against HIV-1-sexual acquisition. The IgA-specific epitope we characterized by reverse vaccinology could help designing a mucosal HIV-1 vaccine.

Identifiants

DOI: 10.1371/journal.ppat.1009103 PMID: 33315937 PMC: PMC7802955
pubmed: 33315937
doi: 10.1371/journal.ppat.1009103
pii: PPATHOGENS-D-20-01478
pmc: PMC7802955
doi:

Substances chimiques

Epitopes, B-Lymphocyte 0
HIV Antibodies 0
HIV Envelope Protein gp41 0
Immunoglobulin A 0
Immunoglobulin G 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e1009103

Déclaration de conflit d'intérêts

The authors have declared that no competing interests exist.

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Auteurs

Marwa Khamassi (M)

Laboratory of Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR 8104, Paris, France.
INSERM U1016, Paris, France.
Université Paris, Paris, France.

Lin Xu (L)

Laboratory of Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR 8104, Paris, France.
INSERM U1016, Paris, France.
Université Paris, Paris, France.

Julien Rey (J)

Université Paris, Paris, France.
Unité de Biologie Fonctionnelle et Adaptative - CNRS UMR 8251 - INSERM ERL U1133, Ressources Parisienne en Bioinformatique Structural, Paris, France.

Maxence Duchemin (M)

Laboratory of Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR 8104, Paris, France.
INSERM U1016, Paris, France.
Université Paris, Paris, France.

Tahar Bouceba (T)

Sorbonne University, CNRS, Institut de Biologie Paris-Seine (IBPS), Protein engineering platform, Molecular Interaction service, Paris, France.

Pierre Tuffery (P)

Université Paris, Paris, France.
Unité de Biologie Fonctionnelle et Adaptative - CNRS UMR 8251 - INSERM ERL U1133, Ressources Parisienne en Bioinformatique Structural, Paris, France.

Daniela Tudor (D)

Laboratory of Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR 8104, Paris, France.
INSERM U1016, Paris, France.
Université Paris, Paris, France.

Morgane Bomsel (M)

Laboratory of Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR 8104, Paris, France.
INSERM U1016, Paris, France.
Université Paris, Paris, France.
ORCID: 0000-0002-9577-7474

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Classifications MeSH

questionsmedicales.fr › Phénomènes du système immunitaire › Spécificité des anticorps › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Phénomènes du système immunitaire › Sites de fixation des anticorps › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Épitopes › Déterminants antigéniques des lymphocytes B › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps antiviraux › Anticorps antideltarétrovirus › Anticorps anti-VIH › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Antigènes viraux › Antigènes du VIH › Protéine d'enveloppe gp41 du VIH › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Maladies du système immunitaire › Déficits immunitaires › Infections à VIH › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Phénomènes du système immunitaire › Séronégativité VIH › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Virus › Virus à ARN › Retroviridae › Lentivirus › Lentivirus des primates › VIH (Virus de l'Immunodéficience Humaine) › VIH-1 (Virus de l'Immunodéficience Humaine de type 1) › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Isotypes des immunoglobulines › Immunoglobuline A › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Isotypes des immunoglobulines › Immunoglobuline G › The CH1α domain of mucosal gp41 IgA...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure tertiaire des protéines › Domaines protéiques › The CH1α domain of mucosal gp41 IgA...