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The conformational epitope of a gp41-specific mucosal protective IgA binds to the HIV-1 envelope and neutralizes infection

Acta Pharmacologica Sinica volume 46, pages 3009–3021 (2025)Cite this article

Abstract

HIV-1 envelope conformational changes necessary for viral infection make the gp41 subunit a key target for antiviral drugs. Using reverse vaccinology applied to a mucosal HIV-1 neutralizing IgA, we identified P7, a 12 amino-acid peptide at the interface of the N and C-helices of gp41. We now show that P7 interacts with the trimeric HIV-1 envelope cross-clade with a nanomolar affinity, captures gp41 in a 6-Helix Bundle conformation, and binds to infected cells and free virus. Functionally, P7 neutralizes HIV infection cross-clade and inhibits cell-to-cell viral transfer. Adding a lipid tail to P7 (Lipo-P7) improved neutralization of primary CD4+ T cells by Transmitted / Founder clade B and primary clades A and C viruses. Lipo-P7 also neutralized a T20-resistant virus harboring gp41 G36D, V38M mutations. Altogether, P7 appears as a promising cross-clade HIV-1 antiviral peptide that could also induce protective mucosal IgA levels to prevent sexual HIV infection.

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Fig. 1: Biotinylated-P7 binds specifically to gp140 of clades A, B, and C.
Fig. 2: P7 binds to HIV-1 envelope expressed on either infected CD4+ T cells or on CEM cells stably expressing an X4 HIV-1 envelope spike.
Fig. 3: P7 inhibits HIV-1 cell-to-cell transmission and viral infection.
Fig. 4: Lipo-P7 neutralizes HIV-1 infection cross-clade and also a T20-resistant mutant virus.

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Funding

This study was supported by grants from l’Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), (AO2022-2-17046), SIDACTION (15CONV03) and Fondation pour la Recherche Médicale (FRM) (Équipe FRM: EQU201903007830) to MB. IS was supported by ANRS, and ACC was supported by the FRM.

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Authors and Affiliations

  1. Laboratory of Mucosal Entry of HIV and Mucosal Immunity Institut Cochin, Paris, France

    Inès Sahnoune, Andréa Cottignies-Calamarte, Annouk Dauvilliers, Kingsley Essemiah, Daniela Tudor & Morgane Bomsel

  2. Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France

    Inès Sahnoune, Andréa Cottignies-Calamarte, Annouk Dauvilliers, Kingsley Essemiah, Daniela Tudor & Morgane Bomsel

  3. Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Kingsley Essemiah

  4. Sorbonne University, CNRS, Institut de Biologie Paris-Seine (IBPS), Protein Engineering Platform, Paris, France

    Tahar Bouceba & Christophe Piesse

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  1. Inès Sahnoune
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  2. Andréa Cottignies-Calamarte
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DT and MB conceived the experiments; IS, ACC, AD, KE, TB, CP, DT, and MB performed and analyzed experiments; DT and MB wrote the manuscript.

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Correspondence to Morgane Bomsel.

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Sahnoune, I., Cottignies-Calamarte, A., Dauvilliers, A. et al. The conformational epitope of a gp41-specific mucosal protective IgA binds to the HIV-1 envelope and neutralizes infection. Acta Pharmacol Sin 46, 3009–3021 (2025). https://doi.org/10.1038/s41401-025-01535-5

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