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<p>HIV-1 envelope glycoproteins (Env) from primary HIV-1 isolates typically adopt a pretriggered “closed” conformation that resists to CD4-induced (CD4i) non-neutralizing antibodies (nnAbs) mediating antibody-dependent cellular cytotoxicity (ADCC). CD4-mimetic compounds (CD4mcs) “open-up” Env allowing binding of CD4i nnAbs, thereby sensitizing HIV-1-infected cells to ADCC. Two families of CD4i nnAbs, the anti-cluster A and anti-coreceptor binding site (CoRBS) Abs, are required to mediate ADCC in combination with the indane CD4mc BNM-III-170. Recently, new indoline CD4mcs with improved potency and breadth have been described. Here, we show that the lead indoline CD4mc, CJF-III-288, sensitizes HIV-1-infected cells to ADCC mediated by anti-CoRBS Abs alone, contributing to improved ADCC activity. When administrated along with the anti-CoRBS 17b, CJF-III-288 delayed viral rebound after ART interruption in HIV-1-infected humanized mice, demonstrating potential for eliciting ADCC in vivo. Structural and conformational analyses reveal that CJF-III-288, in combination with this anti-CoRBS Abs, potently stabilizes an asymmetric “open” State-3 Env conformation. This Env conformation orients the anti-CoRBS Ab to improve ADCC activity and therapeutic potential.</p>

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The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月1日

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  • Jonathan Richard,
  • Michael W. Grunst,
  • Ling Niu,
  • Marco A. Díaz-Salinas,
  • Li Zhu,
  • William D. Tolbert,
  • Lorie Marchitto,
  • Fei Zhou,
  • Catherine Bourassa,
  • Hongil Kim,
  • Sri Lakshmi Tejaswi Boodapati,
  • Derek Yang,
  • Ta Jung Chiu,
  • Hung-Ching Chen,
  • Mehdi Benlarbi,
  • Guillaume Beaudoin-Bussières,
  • Suneetha Gottumukkala,
  • Wenwei Li,
  • Katrina Dionne,
  • Étienne Bélanger,
  • Debashree Chatterjee,
  • Halima Medjahed,
  • Wayne A. Hendrickson,
  • Joseph Sodroski,
  • Zabrina C. Lang,
  • Abraham J. Morton,
  • Rick K. Huang,
  • Doreen Matthies,
  • Amos B. Smith III,
  • Priti Kumar,
  • Walther Mothes,
  • James B. Munro,
  • Marzena Pazgier,
  • Andrés Finzi

摘要

HIV-1 envelope glycoproteins (Env) from primary HIV-1 isolates typically adopt a pretriggered “closed” conformation that resists to CD4-induced (CD4i) non-neutralizing antibodies (nnAbs) mediating antibody-dependent cellular cytotoxicity (ADCC). CD4-mimetic compounds (CD4mcs) “open-up” Env allowing binding of CD4i nnAbs, thereby sensitizing HIV-1-infected cells to ADCC. Two families of CD4i nnAbs, the anti-cluster A and anti-coreceptor binding site (CoRBS) Abs, are required to mediate ADCC in combination with the indane CD4mc BNM-III-170. Recently, new indoline CD4mcs with improved potency and breadth have been described. Here, we show that the lead indoline CD4mc, CJF-III-288, sensitizes HIV-1-infected cells to ADCC mediated by anti-CoRBS Abs alone, contributing to improved ADCC activity. When administrated along with the anti-CoRBS 17b, CJF-III-288 delayed viral rebound after ART interruption in HIV-1-infected humanized mice, demonstrating potential for eliciting ADCC in vivo. Structural and conformational analyses reveal that CJF-III-288, in combination with this anti-CoRBS Abs, potently stabilizes an asymmetric “open” State-3 Env conformation. This Env conformation orients the anti-CoRBS Ab to improve ADCC activity and therapeutic potential.