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| Title | Germline-targeting HIV immunogen induces cross-neutralizing antibodies in outbred macaques. |
|---|---|
| Journal, issue, pages | Immunity, Vol. 59, Issue 4, Page 1140-1160.e11, Year 2026 |
| Publish date | Apr 14, 2026 |
Authors | Nitesh Mishra / Bo Liang / Ryan S Roark / Amrit Raj Ghosh / Sean Callaghan / Wen-Hsin Lee / Xuduo Li / Anh L Vo / Gabriel Avillion / Rohan Roy Chowdhury / Rumi Habib / Frederic Bibollet-Ruche / Gabriella Giese / Prabhgun Oberoi / Khaled Amereh / Anjali Somanathan / Yuxin Zhu / Yuexiu Zhang / Muzaffer Kassab / Lifei Tjio / Sharaf Andrabi / Raphael A Reyes / Joel D Allen / Nicole E James / Kipchoge N Randall / Lara van der Maas / Elana Ben-Akiva / Kasia Kacmarek-Michaels / Samantha Plante / Christian L Martella / Ashwin N Skelly / Ajay Singh / Jonathan Hurtado / Katharina Dueker / Tazio Capozzola / Rebecca Nedellec / Gabriel Ozorowski / Mark G Lewis / Samantha Falcone / Andrea Carfi / Sunny Himansu / Lawrence Shapiro / Max Crispin / Beatrice H Hahn / Bryan Briney / Darrell J Irvine / Dennis R Burton / Andrew B Ward / Facundo D Batista / Peter D Kwong / George M Shaw / Raiees Andrabi / ![]() |
| PubMed Abstract | Germline targeting (GT) is a promising strategy to activate rare broadly neutralizing antibody (bnAb)-producing B cells against HIV, but induction of such responses in outbred animals has not been ...Germline targeting (GT) is a promising strategy to activate rare broadly neutralizing antibody (bnAb)-producing B cells against HIV, but induction of such responses in outbred animals has not been achieved. Using antibody-guided structure-based design, we engineered a GT HIV trimer immunogen, Q23-APEX-GT2, which primes diverse V2-apex bnAb precursors. Q23-APEX-GT2 efficiently activated rare V2-apex-specific B cells in humanized knockin mice and consistently elicited immunofocused antibody responses in outbred rhesus macaques, priming multiple long heavy-chain complementarity-determining region 3 (CDRH3)-loop bnAb-B cell lineages. Monoclonal antibodies isolated from immunized macaques showed broad heterologous HIV trimer recognition and modest cross-neutralization of diverse tier-2 viruses. Cryoelectron microscopy (cryo-EM) structural studies confirmed precise epitope targeting and revealed CDRH3-mediated binding modes that mirrored those of human V2-apex bnAbs. Together, these findings establish proof of principle for priming and early maturation of authentic V2-apex bnAb precursors in outbred macaques and highlight the promise of V2-apex-targeted HIV vaccines. |
External links | Immunity / PubMed:41985438 |
| Methods | EM (single particle) |
| Resolution | 2.9 - 25.0 Å |
| Structure data | ![]() EMDB-49511: CH35 V1V2V3 and gp41-base macaque polyclonal Fabs in complex with Q23-APEX-GT2 trimer ![]() EMDB-49512: CH35 gp41-FP macaque polyclonal Fab in complex with Q23-APEX-GT2 trimer ![]() EMDB-49513: CH70 gp41-GH macaque polyclonal Fab in complex with Q23-APEX-GT2 trimer EMDB-49865, PDB-9nvv: EMDB-49866, PDB-9nvw: EMDB-49867, PDB-9nvx: EMDB-49868, PDB-9nvy: EMDB-49869, PDB-9nvz: EMDB-49870, PDB-9nw0: EMDB-49871, PDB-9nw1: |
| Chemicals | ![]() ChemComp-NAG: ![]() ChemComp-MAN: |
| Source |
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Keywords | VIRAL PROTEIN/IMMUNE SYSTEM / HIV / VIRAL PROTEIN / GERMLINE-TARGETING / IMMUNOGEN / VIRAL PROTEIN-IMMUNE SYSTEM complex / immune complex / neutralization / V2 apex / VIRAL PROTEIN/IMMUE SYSTEM / VIRAL PROTEIN-IMMUE SYSTEM complex |
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human immunodeficiency virus type 1
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