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<p>Efficient priming of B cell precursors is a rate-limiting step in the induction of V2 apex broadly neutralizing antibodies (bNAbs)<sup>1,2</sup>. Here, we describe a novel germline-targeted HIV-1 Env (CAP256.OPT4) that increases the efficiency of V2 apex bNAb precursor priming by 30-400 fold compared with wild-type HIV-1 Envs and induces – in &gt;90% of macaques – neutralization breadth that includes N130-containing viruses. Using three different delivery platforms – persistently replicating simian human immunodeficiency viruses (SHIVs), protein nanoparticles, and mRNA – we show bNAb priming as early as 4 weeks post-infection or immunization, and neutralization breadth in plasma by 12 weeks. In 14 SHIV-infected macaques, neutralization breadth reached as high as 90% on a 21-virus panel with potency as great as 1:20,000 (50% inhibitory dilution, ID<sub>50</sub>). Monoclonal bNAbs isolated from these animals were similarly broad and potent, with cryo-EM structures representing three distinct lineages revealing canonical needle-like HCDR3 binding. Env-Ab coevolution and structural analyses identified five key residues and loop features under positive selection and temporally associated with neutralization breadth. Importantly, prime-boost immunogens designed to capture these features induced broad and potent neutralization of globally diverse viruses including those containing N130 glycan. Further, rhesus bNAbs were not restricted to IGHD3-15*01 heavy chain alleles. These results expand the utility of the rhesus model for HIV-1 vaccine design and provide a molecular blueprint for inducing V2 apex bNAbs in rhesus and humans.</p>

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Enhanced B cell priming induces broadly neutralizing HIV-1 apex antibodies

  • 期刊论文

  • 发表日期：

    2026年6月30日

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  • Lorie Marchitto,
  • Kshitij Wagh,
  • Ryan S. Roark,
  • Severin Coleon,
  • Hui Li,
  • Ashwin N. Skelly,
  • Michael P. Hogarty,
  • Rumi Habib,
  • Wenge Ding,
  • Kasirajan Ayyanathan,
  • Weimin Liu,
  • Zizhang Sheng,
  • Yicheng Guo,
  • Joena Bal,
  • Lena M. Smith,
  • Laura L. Sutherland,
  • Younghoon Park,
  • Andrew J. Connell,
  • Frederic Bibollet-Ruche,
  • Emily Lewis,
  • Samantha J. Plante,
  • Macy J. Akeley,
  • Jinery Lora,
  • Chengyan Zhao,
  • John W. Carey,
  • Christian L. Martella,
  • Yingying Li,
  • Mary S. Campion,
  • Melinda G. Lituchy,
  • Rebecca A. Osbaldeston,
  • Colette G. Gordon,
  • Amie Albertus,
  • Justin Su,
  • Chiaki Noguchi,
  • Ying K. Tam,
  • Christopher Barbosa,
  • Bo Liang,
  • Khaled Amereh,
  • Xuduo Li,
  • Agnes A. Walsh,
  • Darrell J. Irvine,
  • Raiees Andrabi,
  • Robert J. Edwards,
  • Edward F. Kreider,
  • Drew Weissman,
  • Lawrence Shapiro,
  • Peter D. Kwong,
  • Bette T. Korber,
  • Barton F. Haynes,
  • Kevin O. Saunders,
  • Beatrice H. Hahn,
  • George M. Shaw

摘要

Efficient priming of B cell precursors is a rate-limiting step in the induction of V2 apex broadly neutralizing antibodies (bNAbs)1,2. Here, we describe a novel germline-targeted HIV-1 Env (CAP256.OPT4) that increases the efficiency of V2 apex bNAb precursor priming by 30-400 fold compared with wild-type HIV-1 Envs and induces – in >90% of macaques – neutralization breadth that includes N130-containing viruses. Using three different delivery platforms – persistently replicating simian human immunodeficiency viruses (SHIVs), protein nanoparticles, and mRNA – we show bNAb priming as early as 4 weeks post-infection or immunization, and neutralization breadth in plasma by 12 weeks. In 14 SHIV-infected macaques, neutralization breadth reached as high as 90% on a 21-virus panel with potency as great as 1:20,000 (50% inhibitory dilution, ID50). Monoclonal bNAbs isolated from these animals were similarly broad and potent, with cryo-EM structures representing three distinct lineages revealing canonical needle-like HCDR3 binding. Env-Ab coevolution and structural analyses identified five key residues and loop features under positive selection and temporally associated with neutralization breadth. Importantly, prime-boost immunogens designed to capture these features induced broad and potent neutralization of globally diverse viruses including those containing N130 glycan. Further, rhesus bNAbs were not restricted to IGHD3-15*01 heavy chain alleles. These results expand the utility of the rhesus model for HIV-1 vaccine design and provide a molecular blueprint for inducing V2 apex bNAbs in rhesus and humans.