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Elife. 2016 Mar 21;5. pii: e13783. doi: 10.7554/eLife.13783.

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

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
2
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
3
Laboratory of Molecular Immunology, The Rockefeller University, New York, United States.
4
Howard Hughes Medical Institute, The Rockefeller University, New York, United States.

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.

KEYWORDS:

HIV; biophysics; broadly neutralizing antibodies; crystallography; human; immunology; structural biology; virus

PMID:
26997349
PMCID:
PMC4811768
DOI:
10.7554/eLife.13783
[Indexed for MEDLINE]
Free PMC Article

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