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

Author

Listed:
  • Kim-Marie A. Dam

    (California Institute of Technology)

  • Christopher O. Barnes

    (California Institute of Technology
    Stanford University)

  • Harry B. Gristick

    (California Institute of Technology)

  • Till Schoofs

    (The Rockefeller University
    University of Cologne, Faculty of Medicine and University Hospital of Cologne
    Partner Site Bonn–Cologne
    GlaxoSmithKline Vaccines)

  • Priyanthi N. P. Gnanapragasam

    (California Institute of Technology)

  • Michel C. Nussenzweig

    (The Rockefeller University
    Howard Hughes Medical Institute)

  • Pamela J. Bjorkman

    (California Institute of Technology)

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.

Suggested Citation

  • Kim-Marie A. Dam & Christopher O. Barnes & Harry B. Gristick & Till Schoofs & Priyanthi N. P. Gnanapragasam & Michel C. Nussenzweig & Pamela J. Bjorkman, 2022. "HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33860-2
    DOI: 10.1038/s41467-022-33860-2
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    1. Bailey B. Banach & Sergei Pletnev & Adam S. Olia & Kai Xu & Baoshan Zhang & Reda Rawi & Tatsiana Bylund & Nicole A. Doria-Rose & Thuy Duong Nguyen & Ahmed S. Fahad & Myungjin Lee & Bob C. Lin & Tracy , 2023. "Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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