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DOE OSTI · 2423906

HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design

Dam, Kim-Marie A.·Barnes, Christopher O.·Gristick, Harry B.·Schoofs, Till·Gnanapragasam, Priyanthi P.·Nussenzweig, Michel C.·Bjorkman, Pamela J.
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Abstract

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.

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60 APPLIED LIFE SCIENCESCryoelectron microscopyimmunochemistryvaccinesvirus structures

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Dam, Kim-Marie A., Barnes, Christopher O., Gristick, Harry B., Schoofs, Till, Gnanapragasam, Priyanthi P., Nussenzweig, Michel C., Bjorkman, Pamela J.. 2022-10-17. HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design. https://doi.org/10.1038/s41467-022-33860-2

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