9NVV

Cryo-EM structure of V2 apex germline-targeting HIV Env trimer Q23-APEX-GT2

Summary for 9NVV

• Entry DOI: 10.2210/pdb9nvv/pdb
• EMDB information: 49865
• Descriptor: HIV envelope gp120, HIV envelope gp41 ectodomain, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: hiv, viral protein, germline-targeting, immunogen, viral protein-immune system complex, viral protein/immune system
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 6
• Total formula weight: 332394.35

Authors

Roark, R.S.,Shapiro, L.S.,Kwong, P.D. (deposition date: 2025-03-21, release date: 2026-04-01, Last modification date: 2026-04-29)

Primary citation

Mishra, N.,Liang, B.,Roark, R.S.,Ghosh, A.R.,Callaghan, S.,Lee, W.H.,Li, X.,Vo, A.L.,Avillion, G.,Chowdhury, R.R.,Habib, R.,Bibollet-Ruche, F.,Giese, G.,Oberoi, P.,Amereh, K.,Somanathan, A.,Zhu, Y.,Zhang, Y.,Kassab, M.,Tjio, L.,Andrabi, S.,Reyes, R.A.,Allen, J.D.,James, N.E.,Randall Jr., K.N.,van der Maas, L.,Ben-Akiva, E.,Kacmarek-Michaels, K.,Plante, S.,Martella, C.L.,Skelly, A.N.,Singh, A.,Hurtado, J.,Dueker, K.,Capozzola, T.,Nedellec, R.,Ozorowski, G.,Lewis, M.G.,Falcone, S.,Carfi, A.,Himansu, S.,Shapiro, L.,Crispin, M.,Hahn, B.H.,Briney, B.,Irvine, D.J.,Burton, D.R.,Ward, A.B.,Batista, F.D.,Kwong, P.D.,Shaw, G.M.,Andrabi, R.
Germline-targeting HIV immunogen induces cross-neutralizing antibodies in outbred macaques.
Immunity, 59:1140-1160.e11, 2026

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 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.

PubMed: 41985438
DOI: 10.1016/j.immuni.2026.03.012

Experimental method

ELECTRON MICROSCOPY (2.9 Å)