Bacterially derived synthetic mimetics of mammalian oligomannose prime antibody responses that neutralize HIV infectivity

Nat Commun. 2017 Nov 17;8(1):1601. doi: 10.1038/s41467-017-01640-y.

Abstract

Oligomannose-type glycans are among the major targets on the gp120 component of the HIV envelope protein (Env) for broadly neutralizing antibodies (bnAbs). However, attempts to elicit oligomannose-specific nAbs by immunizing with natural or synthetic oligomannose have so far not been successful, possibly due to B cell tolerance checkpoints. Here we design and synthesize oligomannose mimetics, based on the unique chemical structure of a recently identified bacterial lipooligosaccharide, to appear foreign to the immune system. One of these mimetics is bound avidly by members of a family of oligomannose-specific bnAbs and their putative common germline precursor when presented as a glycoconjugate. The crystal structure of one of the mimetics bound to a member of this bnAb family confirms the antigenic resemblance. Lastly, immunization of human-antibody transgenic animals with a lead mimetic evokes nAbs with specificities approaching those of existing bnAbs. These results provide evidence for utilizing antigenic mimicry to elicit oligomannose-specific bnAbs to HIV-1.

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

  • Animals
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / metabolism
  • Bacteria / metabolism
  • CHO Cells
  • Carbohydrate Sequence
  • Cricetulus
  • HEK293 Cells
  • HIV Antibodies / chemistry
  • HIV Antibodies / immunology*
  • HIV Antibodies / metabolism
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / immunology
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / immunology
  • HIV-1 / physiology
  • Humans
  • Mammals / immunology
  • Mammals / metabolism
  • Molecular Mimicry / immunology
  • Oligosaccharides / immunology*
  • Protein Conformation
  • Rats, Transgenic

Substances

  • Antibodies, Neutralizing
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Oligosaccharides