Peer-reviewedCC BY-NC-NDNature
Enhanced B cell priming induces broadly neutralizing HIV-1 apex antibodies
14 affiliations
- 1Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- 2Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA
- 3Aaron Diamond AIDS Research Center, Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
- 4Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA
- 5Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- 6Acuitas Therapeutics, Vancouver, British Columbia, Canada
- 7Department of Immunology and Microbiology, Scripps Research Institure, La Jolla, CA, USA
- 8Howard Hughes Medical Institute, Chevy Chase, MD, USA
- 9Los Alamos National Laboratory, Los Alamos, NM, USA
- 10New Mexico Consortium, Los Alamos, NM, USA
- 11Department of Medicine, Duke University School of Medicine, Durham, NC, USA
- 12Departments of Surgery, Molecular Genetics and Microbiology and Integrative Immunobiology, Duke University School of Medicine, Durham, NC, USA
- 13Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected]
- 14Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected]
Abstract
. Here we describe a 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 over 90% of macaques, neutralization breadth that includes Asn130-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 after infection or immunization, and neutralization breadth in the 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). 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 Asn130 glycan. Furthermore, rhesus bnAbs were not restricted to IGHD3-15*01 heavy-chain alleles. These results expand the use of the rhesus model for HIV-1 vaccine design and provide a molecular blueprint for inducing V2 apex bnAbs in rhesus and humans.
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BibTeX
@article{marchitto2026enhanced,
title = {{Enhanced B cell priming induces broadly neutralizing HIV-1 apex antibodies}},
author = {Lorie Marchitto and Kshitij Wagh and Ryan S. Roark and Séverin Coléon and Hui Li and Ashwin N. Skelly and Michael P. Hogarty and Rumi Habib and Wenge Ding and Kasirajan Ayyanathan and Weimin Liu and Zizhang Sheng and Yicheng Guo and Joena Bal and Lena M. Smith and Laura L. Sutherland and Younghoon Park and Andrew Jesse Connell and Frédéric Bibollet‐Ruche and Emily E. Lewis and Samantha J. Plante and Macy J Akeley and Jinery Lora and Chengyan Zhao and John W. Carey and Christian L. Martella and Yingying Li and Mary S. Campion and Melinda G Lituchy and Rebecca A Osbaldeston and Colette G. Gordon and Amie Albertus and Justin Su and Chiaki Noguchi and Ying K. Tam and Christopher Barbosa and Bo Liang and Khaled Amereh and Xuduo Li and Agnes A. Walsh and Darrell J. Irvine and Raiees Andrabi and Robert J. Edwards and Edward F. Kreider and Drew Weissman and Lawrence S. Shapiro and Peter D. Kwong and Bette Korber and Barton F. Haynes and Kevin O. Saunders and Beatrice H. Hahn and George M. Shaw},
journal = {Nature},
year = {2026},
month = jun,
doi = {10.1038/s41586-026-10838-4},
url = {https://doi.org/10.1038/s41586-026-10838-4},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Enhanced B cell priming induces broadly neutralizing HIV-1 apex antibodies
AU - Lorie Marchitto
AU - Kshitij Wagh
AU - Ryan S. Roark
AU - Séverin Coléon
AU - Hui Li
AU - Ashwin N. Skelly
AU - Michael P. Hogarty
AU - Rumi Habib
AU - Wenge Ding
AU - Kasirajan Ayyanathan
AU - Weimin Liu
AU - Zizhang Sheng
AU - Yicheng Guo
AU - Joena Bal
AU - Lena M. Smith
AU - Laura L. Sutherland
AU - Younghoon Park
AU - Andrew Jesse Connell
AU - Frédéric Bibollet‐Ruche
AU - Emily E. Lewis
AU - Samantha J. Plante
AU - Macy J Akeley
AU - Jinery Lora
AU - Chengyan Zhao
AU - John W. Carey
AU - Christian L. Martella
AU - Yingying Li
AU - Mary S. Campion
AU - Melinda G Lituchy
AU - Rebecca A Osbaldeston
AU - Colette G. Gordon
AU - Amie Albertus
AU - Justin Su
AU - Chiaki Noguchi
AU - Ying K. Tam
AU - Christopher Barbosa
AU - Bo Liang
AU - Khaled Amereh
AU - Xuduo Li
AU - Agnes A. Walsh
AU - Darrell J. Irvine
AU - Raiees Andrabi
AU - Robert J. Edwards
AU - Edward F. Kreider
AU - Drew Weissman
AU - Lawrence S. Shapiro
AU - Peter D. Kwong
AU - Bette Korber
AU - Barton F. Haynes
AU - Kevin O. Saunders
AU - Beatrice H. Hahn
AU - George M. Shaw
PY - 2026
DA - 2026/06/30
JO - Nature
DO - 10.1038/s41586-026-10838-4
UR - https://doi.org/10.1038/s41586-026-10838-4
AB - . Here we describe a 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 over 90% of macaques, neutralization breadth that includes Asn130-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 after infection or immunization, and neutralization breadth in the 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). 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 Asn130 glycan. Furthermore, rhesus bnAbs were not restricted to IGHD3-15*01 heavy-chain alleles. These results expand the use of the rhesus model for HIV-1 vaccine design and provide a molecular blueprint for inducing V2 apex bnAbs in rhesus and humans.
SN - 0028-0836
SN - 1476-4687
ER -