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TitleEnhanced B cell priming induces broadly neutralizing HIV-1 apex antibodies.
Journal, issue, pagesNature, Year 2026
Publish dateJun 30, 2026
AuthorsLorie 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 /
PubMed AbstractEfficient priming of B cell precursors is a rate-limiting step in the induction of V2 apex broadly neutralizing antibodies (bNAbs). Here, we describe a novel germline-targeted HIV-1 Env (CAP256.OPT4) ...Efficient priming of B cell precursors is a rate-limiting step in the induction of V2 apex broadly neutralizing antibodies (bNAbs). 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, ID). 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.
External linksNature / PubMed:42380659
MethodsEM (single particle)
Resolution2.9 - 3.3 Å
Structure data

74654

9zrx

EMDB-74654, PDB-9zrx:
Cryo-EM structure of SHIV-elicited CE79-1571 Fab in complex with HIV Env trimer Q23-SCT27
Method: EM (single particle) / Resolution: 3.3 Å

74655

9zry

EMDB-74655, PDB-9zry:
Cryo-EM structure of SHIV-elicited CN81-2029 Fab in complex with HIV Env trimer Q23-SCT27
Method: EM (single particle) / Resolution: 2.9 Å

74656

9zrz

EMDB-74656, PDB-9zrz:
Cryo-EM structure of SHIV-elicited CI93-1365 Fab in complex with HIV Env trimer Q23-SCT27
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • macaca mulatta (Rhesus monkey)
  • human immunodeficiency virus
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Neutralizing antibody / HIV V2 apex / SHIV-elicited / Immune complex / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / SHIV / neutralization

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