An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions.
The conserved oligomannose epitope, Man(9)GlcNAc(2), recognized by the broadly neutralizing human mAb 2G12 is an attractive prophylactic vaccine candidate for the prevention of HIV-1 infection. We recently reported total chemical synthesis of a series of glycopeptides incorporating one to three copies of Man(9)GlcNAc(2) coupled to a cyclic peptide scaffold. Surface plasmon resonance studies showed that divalent and trivalent, but not monovalent, compounds were capable of binding 2G12. To test the efficacy of the divalent glycopeptide as an immunogen capable of inducing a 2G12-like neutralizing antibody response, we covalently coupled the molecule to a powerful immune-stimulating protein carrier and evaluated immunogenicity of the conjugate in two animal species. We used a differential immunoassay to demonstrate induction of high levels of carbohydrate-specific antibodies; however, these antibodies showed poor recognition of recombinant gp160 and failed to neutralize a panel of viral isolates in entry-based neutralization assays. To ascertain whether antibodies produced during natural infection could recognize the mimetics, we screened a panel of HIV-1-positive and -negative sera for binding to gp120 and the synthetic antigens. We present evidence from both direct and competitive binding assays that no significant recognition of the glycopeptides was observed, although certain sera did contain antibodies that could compete with 2G12 for binding to recombinant gp120.
Department of Vaccines Basic Research, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA. joseph_joyce@merck.com
Joseph G
JG
Joyce
Isaac J
IJ
Krauss
Hong C
HC
Song
David W
DW
Opalka
Karen M
KM
Grimm
Deborah D
DD
Nahas
Mark T
MT
Esser
Renee
R
Hrin
Meizhen
M
Feng
Vadim Y
VY
Dudkin
Michael
M
Chastain
John W
JW
Shiver
Samuel J
SJ
Danishefsky
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000918:Antibody Specificity; D001667:Binding, Competitive / Q000276:immunology; D006020:Glycopeptides / Q000138:chemical synthesis / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D018716:Molecular Mimicry; D009500:Neutralization Tests; D009844:Oligosaccharides / Q000276:immunology*; D014771:Virion / Q000276:immunology
D000906:Antibodies; D006020:Glycopeptides; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D009844:Oligosaccharides