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HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design
BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4...
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Published in: | Nature communications 2022-10, Vol.13 (1), p.6123-12, Article 6123 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4.1 Å and 3.4 Å single-particle cryo-EM structures of two inferred germline (iGL) BG24 precursors complexed with engineered Env-based immunogens lacking CD4bs N-glycans. Structures reveal critical Env contacts by BG24
iGL
and identify antibody light chain structural features that impede Env recognition. In addition, biochemical data and cryo-EM structures of BG24
iGL
variants bound to Envs with CD4bs glycans present provide insights into N-glycan accommodation, including structural modes of light chain adaptations in the presence of the N276
gp120
glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design.
VRC01-class bNAbs against the CD4 binding site of HIV-1 Env are targets of vaccine design. Here, the authors structurally characterized germline versions of the VRC01-class bNAb, BG24, bound to Env. They reveal mechanisms of germline binding, informing the design of VRC01-class targeting immunogens. |
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ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-022-33860-2 |