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

Kim-Marie A. Dam, Christopher O. Barnes, Harry B. Gristick, Till Schoofs, Priyanthi N. P. Gnanapragasam, Michel C. Nussenzweig and Pamela J. Bjorkman ()
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Kim-Marie A. Dam: California Institute of Technology
Christopher O. Barnes: California Institute of Technology
Harry B. Gristick: California Institute of Technology
Till Schoofs: The Rockefeller University
Priyanthi N. P. Gnanapragasam: California Institute of Technology
Michel C. Nussenzweig: The Rockefeller University
Pamela J. Bjorkman: California Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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 BG24iGL and identify antibody light chain structural features that impede Env recognition. In addition, biochemical data and cryo-EM structures of BG24iGL 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 N276gp120 glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design.

Date: 2022
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DOI: 10.1038/s41467-022-33860-2

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