HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen

Science. 2016 Mar 25;351(6280):1458-63. doi: 10.1126/science.aad9195.

Abstract

Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naïve B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. Using deep mutational scanning and multitarget optimization, we developed a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naïve B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen as a candidate human vaccine prime. These methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AIDS Vaccines / immunology*
  • Amino Acid Sequence
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / isolation & purification
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / isolation & purification
  • Antibody Affinity
  • B-Lymphocytes / immunology
  • Broadly Neutralizing Antibodies
  • Cell Separation
  • Combinatorial Chemistry Techniques
  • Epitopes, B-Lymphocyte / chemistry
  • Epitopes, B-Lymphocyte / genetics
  • Epitopes, B-Lymphocyte / immunology*
  • Germ Cells / immunology*
  • HIV Antibodies / chemistry
  • HIV Antibodies / immunology*
  • HIV Antibodies / isolation & purification
  • HIV-1 / immunology*
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Peptide Library
  • Precursor Cells, B-Lymphoid / immunology*
  • Protein Conformation

Substances

  • AIDS Vaccines
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Broadly Neutralizing Antibodies
  • Epitopes, B-Lymphocyte
  • HIV Antibodies
  • Peptide Library
  • VRC01 monoclonal antibody

Associated data

  • GENBANK/KU760929
  • GENBANK/KU760930
  • GENBANK/KU760931
  • GENBANK/KU760932
  • GENBANK/KU760933
  • GENBANK/KU760934
  • GENBANK/KU760935
  • GENBANK/KU760936
  • GENBANK/KU760937
  • GENBANK/KU760938
  • GENBANK/KU760939
  • GENBANK/KU760940
  • GENBANK/KU760941
  • GENBANK/KU760942
  • GENBANK/KU760943
  • GENBANK/KU760944
  • GENBANK/KU760945
  • GENBANK/KU760946
  • GENBANK/KU760947
  • GENBANK/KU760948
  • GENBANK/KU760949
  • GENBANK/KU760950
  • GENBANK/KU760951
  • GENBANK/KU760952
  • GENBANK/KU760953
  • GENBANK/KU760954
  • GENBANK/KU760955
  • GENBANK/KU760956
  • GENBANK/KU760957
  • GENBANK/KU760958
  • GENBANK/KU760959
  • GENBANK/KU760960
  • GENBANK/KU760961
  • GENBANK/KU760962
  • GENBANK/KU760963
  • GENBANK/KU760964
  • GENBANK/KU760965
  • GENBANK/KU760966
  • GENBANK/KU760967
  • GENBANK/KU760968
  • GENBANK/KU760969
  • GENBANK/KU760970
  • GENBANK/KU760971
  • GENBANK/KU760972
  • GENBANK/KU760973
  • GENBANK/KU760974
  • GENBANK/KU760975
  • GENBANK/KU760976
  • GENBANK/KU760977
  • GENBANK/KU760978
  • GENBANK/KU760979
  • GENBANK/KU760980
  • GENBANK/KU760981
  • GENBANK/KU760982
  • PDB/5IES
  • PDB/5IF0
  • PDB/5IFA