Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies

Immunity. 2013 Aug 22;39(2):245-58. doi: 10.1016/j.immuni.2013.04.012. Epub 2013 Aug 1.

Abstract

Antibodies of the VRC01 class neutralize HIV-1, arise in diverse HIV-1-infected donors, and are potential templates for an effective HIV-1 vaccine. However, the stochastic processes that generate repertoires in each individual of >10(12) antibodies make elicitation of specific antibodies uncertain. Here we determine the ontogeny of the VRC01 class by crystallography and next-generation sequencing. Despite antibody-sequence differences exceeding 50%, antibody-gp120 cocrystal structures reveal VRC01-class recognition to be remarkably similar. B cell transcripts indicate that VRC01-class antibodies require few specific genetic elements, suggesting that naive-B cells with VRC01-class features are generated regularly by recombination. Virtually all of these fail to mature, however, with only a few-likely one-ancestor B cell expanding to form a VRC01-class lineage in each donor. Developmental similarities in multiple donors thus reveal the generation of VRC01-class antibodies to be reproducible in principle, thereby providing a framework for attempts to elicit similar antibodies in the general population.

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Monoclonal / genetics*
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Neutralizing / immunology
  • B-Lymphocytes / immunology
  • Base Sequence
  • Broadly Neutralizing Antibodies
  • Crystallography, X-Ray
  • HIV Antibodies / genetics*
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / immunology
  • HIV Infections / immunology
  • HIV-1 / immunology*
  • Humans
  • Leukocytes, Mononuclear
  • Molecular Sequence Data
  • Sequence Analysis, DNA

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Broadly Neutralizing Antibodies
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • VRC01 monoclonal antibody
  • gp120 protein, Human immunodeficiency virus 1

Associated data

  • GENBANK/KC848679
  • GENBANK/KC848680
  • GENBANK/KC848681
  • GENBANK/KC848682
  • GENBANK/KC848683
  • GENBANK/KC848684
  • GENBANK/KC848685
  • GENBANK/KC848686
  • GENBANK/KC848687
  • GENBANK/KC848688
  • GENBANK/KC848689
  • GENBANK/KC848690
  • GENBANK/KC848691
  • GENBANK/KC848692
  • GENBANK/KC848693
  • GENBANK/KC848694
  • GENBANK/KC848695
  • GENBANK/KC848696
  • GENBANK/KC848697
  • GENBANK/KC848698
  • GENBANK/KC848699
  • GENBANK/KC848700
  • GENBANK/KC848701
  • GENBANK/KC848702
  • GENBANK/KC848703
  • GENBANK/KC848704
  • GENBANK/KC848705
  • GENBANK/KC848706
  • GENBANK/KC848707
  • GENBANK/KC848708
  • GENBANK/KC848709
  • GENBANK/KC848710
  • PDB/4JPV
  • PDB/4JPW
  • PDB/4LSP
  • PDB/4LSQ
  • PDB/4LSR
  • PDB/4LSS
  • PDB/4LST
  • PDB/4LSU
  • PDB/4LSV