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<p>Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels. 007 targets an N332<sub>gp120</sub> glycan-independent V3 epitope, a site of the HIV-1 envelope protein (Env) vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryogenic electron microscopy structure revealed contacts with the V3 <sup>324</sup>GD/NIR<sup>327</sup> motif and interactions with N156<sub>gp120</sub> and N301<sub>gp120</sub> glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332<sub>gp120</sub> glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs. Bivalent 007 IgG was more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1<sub>ADA</sub>-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007’s potential for HIV-1 prevention, therapy, functional cure and vaccine design.</p>

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Identification of a potent V3 glycan site broadly neutralizing antibody targeting an N332gp120 glycan-independent epitope

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月3日

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  • Lutz Gieselmann,
  • Andrew T. DeLaitsch,
  • Malena Rohde,
  • Caelan Radford,
  • Johanna Worczinski,
  • Anna Ashurov,
  • Elvin Ahmadov,
  • Judith A. Burger,
  • Colin Havenar-Daughton,
  • Sharvari Deshpande,
  • Federico Giovannoni,
  • Davide Corti,
  • Christoph Kreer,
  • Meryem Seda Ercanoglu,
  • Philipp Schommers,
  • Ivelin S. Georgiev,
  • Anthony P. West Jr.,
  • Jacqueline Knüfer,
  • Ricarda Stumpf,
  • Arne Kroidl,
  • Christof Geldmacher,
  • Lucas Maganga,
  • Wiston William,
  • Nyanda E. Ntinginya,
  • Michael Hoelscher,
  • Zhengrong Yang,
  • Qing Wei,
  • Matthew B. Renfrow,
  • Todd J. Green,
  • Jan Novak,
  • Marit J. van Gils,
  • Harry B. Gristick,
  • Henning Gruell,
  • Jesse D. Bloom,
  • Michael S. Seaman,
  • Pamela J. Bjorkman,
  • Florian Klein

摘要

Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels. 007 targets an N332gp120 glycan-independent V3 epitope, a site of the HIV-1 envelope protein (Env) vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryogenic electron microscopy structure revealed contacts with the V3 324GD/NIR327 motif and interactions with N156gp120 and N301gp120 glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332gp120 glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs. Bivalent 007 IgG was more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1ADA-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007’s potential for HIV-1 prevention, therapy, functional cure and vaccine design.