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Structural basis for germline antibody recognition of HIV-1 immunogens.

  • Author(s): Scharf, Louise;
  • West, Anthony P;
  • Sievers, Stuart A;
  • Chen, Courtney;
  • Jiang, Siduo;
  • Gao, Han;
  • Gray, Matthew D;
  • McGuire, Andrew T;
  • Scheid, Johannes F;
  • Nussenzweig, Michel C;
  • Stamatatos, Leonidas;
  • Bjorkman, Pamela J
  • et al.
Abstract

Efforts to elicit broadly neutralizing antibodies (bNAbs) against HIV-1 require understanding germline bNAb recognition of HIV-1 envelope glycoprotein (Env). The VRC01-class bNAb family derived from the VH1-2*02 germline allele arose in multiple HIV-1-infected donors, yet targets the CD4-binding site on Env with common interactions. Modified forms of the 426c Env that activate germline-reverted B cell receptors are candidate immunogens for eliciting VRC01-class bNAbs. We present structures of germline-reverted VRC01-class bNAbs alone and complexed with 426c-based gp120 immunogens. Germline bNAb-426c gp120 complexes showed preservation of VRC01-class signature residues and gp120 contacts, but detectably different binding modes compared to mature bNAb-gp120 complexes. Unlike typical antibody-antigen interactions, VRC01-class germline antibodies exhibited preformed antigen-binding conformations for recognizing immunogens. Affinity maturation introduced substitutions increasing induced-fit recognition and electropositivity, potentially to accommodate negatively-charged complex-type N-glycans on gp120. These results provide general principles relevant to the unusual evolution of VRC01-class bNAbs and guidelines for structure-based immunogen design.

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