Comparative high-resolution Cryo-Electron Microscopy reveals distinct binding modes and glycan dependencies of glycan-V3-specific HIV-1 broadly neutralizing antibodies

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B959
Abstract ID: 7478

Presenting Author:
Amirabbas Maghsoudi , Postbaccalaureate Fellow at NIAID, NIH

Abstract:

The identification and characterization of HIV-1 broadly neutralizing antibodies (bNAbs), defined as those that neutralize multiple globally distributed strains of HIV-1, continue to inform the design of HIV vaccines and therapeutics. Here we characterize the binding requirements of three bNAb lineages that target the glycan-V3 epitope on the HIV-1 spike glycoprotein: VRC24, VRC29, and VRC41. VRC24 and VRC29 were previously identified from North American donors N27 and N170, respectively, while VRC41 was isolated from African donor CH0765. The cryo-electron microscopy structures of VRC24, VRC29, and VRC41 in complex with BG505.W6M.C2 Env trimer with a T332N glycan knock-in mutation were each determined at 3.1 angstroms resolution. The study uncovered key antibody binding preferences to glycans at positions 301 and 332 of the spike, along with a notable conserved GDIR motif at positions 324-327 within the V3 region. Additionally, VRC24 and VRC29 exhibited engagement with an additional glycan at position 156, while VRC41 instead contacted a glycan at position 137. Moreover, VRC29 and VRC24 employ both heavy and light chains for binding, contrasting with VRC24's predominant reliance on the heavy chain for effective binding. These findings highlight the diverse HIV-1 spike-binding modes of glycan-V3-specific bNAbs and raise the potential for complementarity of different bNAbs targeting the same region of Env in vaccine-elicited responses or in therapeutic settings.