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<p>Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by envelope diversity and rapid viral escape. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies with highest antiviral activity. From 831 expressed monoclonal antibodies, we identified 04_A06, a V<sub>H</sub>1-2-encoded broadly neutralizing antibody to the CD4 binding site with remarkable breadth and potency against multiclade pseudovirus panels (geometric mean half-maximal inhibitory concentration = 0.059 µg ml<sup>−1</sup>, breadth = 98.5%, 332 strains). Moreover, 04_A06 was not susceptible to classic CD4 binding site escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed an unusually long 11-amino-acid heavy chain insertion that facilitates interprotomer contacts with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody-Mediated Prevention trials (geometric mean half-maximal inhibitory concentration = 0.082 µg ml<sup>−1</sup>, breadth = 98.4%, 191 virus strains), and in silico modeling for 04_A06LS predicted prevention efficacy of &gt;93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention of HIV-1 infection.</p>

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Profiling of HIV-1 elite neutralizer cohort reveals a CD4bs bnAb for HIV-1 prevention and therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Lutz Gieselmann,
  • Andrew T. DeLaitsch,
  • Malena Rohde,
  • Henning Gruell,
  • Christoph Kreer,
  • Meryem Seda Ercanoglu,
  • Harry B. Gristick,
  • Philipp Schommers,
  • Elvin Ahmadov,
  • Caelan Radford,
  • Andrea Mazzolini,
  • Lily Zhang,
  • Anthony P. West Jr,
  • Johanna Worczinski,
  • Anna Ashurov,
  • Maren L. Reichwein,
  • Jacqueline Knüfer,
  • Ricarda Stumpf,
  • Nonhlanhla N. Mkhize,
  • Haajira Kaldine,
  • Sinethemba Bhebhe,
  • Sharvari Deshpande,
  • Federico Giovannoni,
  • Erin Stefanutti,
  • Fabio Benigni,
  • Colin Havenar-Daughton,
  • Davide Corti,
  • Arne Kroidl,
  • Anurag Adhikari,
  • Aubin J. Nanfack,
  • Georgia E. Ambada,
  • Ralf Duerr,
  • Lucas Maganga,
  • Wiston William,
  • Nyanda E. Ntinginya,
  • Timo Wolf,
  • Christof Geldmacher,
  • Michael Hoelscher,
  • Clara Lehmann,
  • Penny L. Moore,
  • Thierry Mora,
  • Aleksandra M. Walczak,
  • Peter B. Gilbert,
  • Nicole A. Doria-Rose,
  • Yunda Huang,
  • Jesse D. Bloom,
  • Michael S. Seaman,
  • Pamela J. Bjorkman,
  • Florian Klein

摘要

Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by envelope diversity and rapid viral escape. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies with highest antiviral activity. From 831 expressed monoclonal antibodies, we identified 04_A06, a VH1-2-encoded broadly neutralizing antibody to the CD4 binding site with remarkable breadth and potency against multiclade pseudovirus panels (geometric mean half-maximal inhibitory concentration = 0.059 µg ml−1, breadth = 98.5%, 332 strains). Moreover, 04_A06 was not susceptible to classic CD4 binding site escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed an unusually long 11-amino-acid heavy chain insertion that facilitates interprotomer contacts with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody-Mediated Prevention trials (geometric mean half-maximal inhibitory concentration = 0.082 µg ml−1, breadth = 98.4%, 191 virus strains), and in silico modeling for 04_A06LS predicted prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention of HIV-1 infection.