Sahnoune Inès, Cottignies-Calamarte Andréa, Dauvilliers Annouk, Essemiah Kingsley, Bouceba Tahar, Piesse Christophe, Tudor Daniela, Bomsel Morgane
Laboratory of Mucosal Entry of HIV and Mucosal Immunity Institut Cochin, Paris, France.
Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France.
Acta Pharmacol Sin. 2025 Jun 5. doi: 10.1038/s41401-025-01535-5.
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.
HIV-1感染所需的包膜构象变化使gp41亚基成为抗病毒药物的关键靶点。通过将反向疫苗学应用于黏膜HIV-1中和性IgA，我们鉴定出P7，这是一种位于gp41的N螺旋和C螺旋界面的12个氨基酸的肽段。我们现在表明，P7以纳摩尔亲和力与三聚体HIV-1包膜跨亚型相互作用，捕获处于6螺旋束构象的gp41，并与受感染细胞和游离病毒结合。在功能上，P7可中和跨亚型的HIV感染并抑制细胞间病毒转移。给P7添加脂质尾（Lipo-P7）可增强B亚型传播/奠基者毒株以及A亚型和C亚型原代病毒对原代CD4 T细胞的中和作用。Lipo-P7还可中和携带gp41 G36D、V38M突变的T20耐药病毒。总之，P7似乎是一种很有前景的跨亚型HIV-1抗病毒肽，它还可诱导保护性黏膜IgA水平以预防性传播HIV感染。
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