An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions Journal Article
| Authors: | Joyce, J. G.; Krauss, I. J.; Song, H. C.; Opalka, D. W.; Grimm, K. M.; Nahas, D. D.; Esser, M. T.; Hrin, R.; Feng, M.; Dudkin, V. Y.; Chastain, M.; Shiver, J. W.; Danishefsky, S. J. |
| Article Title: | An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions |
| Abstract: | The conserved oligomannose epitope, Man9GlcNAc2, 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 Man9GlcNAc2 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. © 2008 by The National Academy of Sciences of the USA. |
| Keywords: | controlled study; unclassified drug; nonhuman; animals; infection; animal experiment; protein binding; drug structure; drug screening; drug synthesis; animalia; drug dose escalation; antigen; prophylaxis; molecular recognition; immunogenicity; antibody response; recombinant protein; antibody specificity; immunoassay; immunostimulation; antibodies; surface plasmon resonance; drug binding; glycopeptides; cyclopeptide; carbohydrate; binding competition; human immunodeficiency virus 1; hiv-1; immunization; oligosaccharide; oligosaccharides; molecule; binding, competitive; neutralizing antibody; human immunodeficiency virus 1 infection; virion; virus neutralization; covalent bond; binding assay; conjugate; molecular mimicry; human immunodeficiency virus vaccine; recombinant glycoprotein gp 120; recombinant glycoprotein gp 120 human immunodeficiency virus 1 2g12 mimotope conjugate vaccine; recombinant glycoprotein gp 160; recombinant glycoprotein gp 160 human immunodeficiency virus 1 2g12 mimotope conjugate vaccine; recombinant glycoprotein gp 41; recombinant glycoprotein gp 41 human immunodeficiency virus 1 2g12 mimotope conjugate vaccine; recombinant glycoprotein p 24; recombinant glycoprotein p 24 human immunodeficiency virus 1 2g12 mimotope conjugate vaccine; guinea pig; hiv antibodies; hiv envelope protein gp120; neutralization tests |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 105 |
| Issue: | 41 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2008-10-01 |
| Start Page: | 15684 |
| End Page: | 15689 |
| Language: | English |
| DOI: | 10.1073/pnas.0807837105 |
| PUBMED: | 18838688 |
| PROVIDER: | scopus |
| PMCID: | PMC2562416 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 28" - "Export Date: 17 November 2011" - "CODEN: PNASA" - "Source: Scopus" |
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