9CU5

LJF-085 Fab in complex with HIV Env JRFL NFL TD CC3+ trimer and 35O22 Fab

Summary for 9CU5

• Entry DOI: 10.2210/pdb9cu5/pdb
• EMDB information: 45928
• Descriptor: 35O22 heavy chain Fv, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• Functional Keywords: nhp, rhesus macaque, gp120 interface, hiv, nfl, neutralizing antibody, viral protein-immune system complex, viral protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 13
• Total formula weight: 365213.10

Authors

Ozorowski, G.,Ward, A.B. (deposition date: 2024-07-25, release date: 2025-05-21, Last modification date: 2025-06-25)

Primary citation

Schleich, F.A.,Bale, S.,Guenaga, J.,Ozorowski, G.,Adori, M.,Lin, X.,Castro Dopico, X.,Wilson, R.,Chernyshev, M.,Cotgreave, A.T.,Mandolesi, M.,Cluff, J.,Doyle, E.D.,Sewall, L.M.,Lee, W.H.,Zhang, S.,O'Dell, S.,Healy, B.S.,Lim, D.,Lewis, V.R.,Ben-Akiva, E.,Irvine, D.J.,Doria-Rose, N.A.,Corcoran, M.,Carnathan, D.,Silvestri, G.,Wilson, I.A.,Ward, A.B.,Karlsson Hedestam, G.B.,Wyatt, R.T.
Vaccination of nonhuman primates elicits a broadly neutralizing antibody lineage targeting a quaternary epitope on the HIV-1 Env trimer.
Immunity, 58:1598-, 2025

PubMed Abstract: The elicitation of cross-neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) by vaccination remains a major challenge. Here, we immunized previously Env-immunized nonhuman primates with a series of near-native trimers that possessed N-glycan deletions proximal to the conserved CD4 binding site (CD4bs) to focus B cells to this region. Following heterologous boosting with fully glycosylated trimers, we detected tier 2 cross-neutralizing activity in the serum of several animals. Isolation of 185 matched heavy- and light-chain sequences from Env-binding memory B cells from an early responder identified a broadly neutralizing antibody lineage, LJF-0034, which neutralized nearly 70% of an 84-member HIV-1 global panel. High-resolution cryoelectron microscopy (cryo-EM) structures revealed a bifurcated binding mode that bridged the CD4bs to V3 across the gp120:120 interface on two adjacent protomers, evading the proximal N276 glycan impediment to the CD4bs, allowing neutralization breadth. This quaternary epitope defines a potential target for future HIV-1 vaccine development.

PubMed: 40339576
DOI: 10.1016/j.immuni.2025.04.010

Experimental method

ELECTRON MICROSCOPY (3.4 Å)