Synthetic HIV V3 Glycopeptide Immunogen Carrying a N334 N-Glycan Induces Glycan-Dependent Antibodies with Promiscuous Site Recognition

J Med Chem. 2018 Nov 21;61(22):10116-10125. doi: 10.1021/acs.jmedchem.8b01290. Epub 2018 Nov 8.

Abstract

The N332 high-mannose glycan on the HIV-1 gp120 V3-loop is the target of many bNAbs. About 17% HIV isolates carry the N332 to N334 mutation, but the antibody recognition of the N334 N-glycan and its immunogenicity are not well characterized. Here we report the chemoenzymatic synthesis, antigenicity, and immunogenicity of the V3 N334 glycopeptides from HIV-1 A244 gp120, a key component in the partially successful Thai clinical trials. We found that synthetic V3 glycopeptide carrying a N334 high-mannose glycan could be recognized by bNAb PGT128 and PGT126 but not by 10-1074. Rabbit immunization with the synthetic three-component A244 glycopeptide immunogen elicited substantial glycan-dependent antibodies with broad reactivity to various HIV-1 gp120/gp140 carrying N332 or N334 glycosylation sites. These results indicated that the N334 site is vulnerable and the A244 V3 glycopeptide represents a valuable immunogen for further HIV-1 vaccine studies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Viral / immunology*
  • Binding Sites
  • Chemistry Techniques, Synthetic
  • Female
  • Glycopeptides / chemical synthesis*
  • Glycopeptides / chemistry
  • Glycopeptides / immunology*
  • Glycosylation
  • HIV Envelope Protein gp120 / chemistry*
  • Immunization
  • Models, Molecular
  • Polysaccharides / chemistry*
  • Protein Conformation
  • Rabbits
  • Substrate Specificity
  • env Gene Products, Human Immunodeficiency Virus / immunology

Substances

  • Antibodies, Viral
  • Glycopeptides
  • HIV Envelope Protein gp120
  • Polysaccharides
  • env Gene Products, Human Immunodeficiency Virus
  • gp120 protein, Human immunodeficiency virus 1
  • gp140 envelope protein, Human immunodeficiency virus 1