title: Structural basis for germline antibody recognition of HIV-1 immunogens.
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.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Louise
authors.initials: L
authors.lastname: Scharf
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: West
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Sievers
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Courtney
authors.initials: C
authors.lastname: Chen
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Siduo
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Han
authors.initials: H
authors.lastname: Gao
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Gray
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: McGuire
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, United States.
authors.forename: Johannes F
authors.initials: JF
authors.lastname: Scheid
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, United States.|Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Bjorkman
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D018360:Crystallography, X-Ray; D015483:HIV Antibodies / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015488:HIV Antigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120
keywords: HIV; biophysics; broadly neutralizing antibodies; crystallography; human; immunology; structural biology; virus