Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 May 23;4(5):582-589.
doi: 10.1021/acscentsci.8b00060. Epub 2018 May 7.

Multivalent Antigen Presentation Enhances the Immunogenicity of a Synthetic Three-Component HIV-1 V3 Glycopeptide Vaccine

Hui Cai  1 , Roushu Zhang  1 , Jared Orwenyo  1 , John Giddens  1 , Qiang Yang  1 , Celia C LaBranche  2 , David C Montefiori  2 , Lai-Xi Wang  1
Affiliations

Multivalent Antigen Presentation Enhances the Immunogenicity of a Synthetic Three-Component HIV-1 V3 Glycopeptide Vaccine

Hui Cai et al. ACS Cent Sci. .

Abstract

HIV-1 envelope glycoproteins gp120 and gp41 are presented on the virus surface as a trimer of heterodimer and are the targets of broadly neutralizing antibodies (bNAbs). We describe here the synthesis and preliminary immunological evaluation of a three-component trivalent HIV-1 V3 glycopeptide immunogen aiming to raise glycopeptide epitope-specific antibodies. Click chemistry confers efficient synthesis of the lipopeptide-glycopeptide conjugate that carries three copies of HIV-1 JR-FL gp120 V3 glycopeptide with a high-mannose glycan at the N332 glycosylation site. We found that the multivalent presentation substantially enhanced the immunogenicity of the V3 glycopeptide. The antisera induced by the three-component multivalent glycopeptide immunogen exhibited stronger binding to heterologous HIV-1 gp120s and the trimeric gp140s than that from the monovalent glycopeptide immunogen. The antisera generated from this preliminary rabbit immunization did not show virus neutralization activity, probably due to the lack of somatic maturation. The ability to elicit substantial glycopeptide epitope-specific antibodies by the three-component trivalent glycopeptide immunogen suggests that it could serve as a valuable vaccine component in combination with other vaccine candidates for further immunization studies.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. (a) Structure of the Three-Component Monovalent Glycopeptide Immunogen, and (b) Synthesis of Three-Component Trivalent Glycopeptide Immunogen
Figure 1
Figure 1
HPLC and ESI-MS analysis of the synthetic three-component trivalent glycopeptide immunogen. (a) Trivalent lipopeptide scaffold 2. (b) Three-component trivalent glycopeptide immunogen 4. Left panel, analytical HPLC profile; right panel, the deconvoluted ESI-MS spectra. Analytical HPLC were run on a CN column using a linear gradient of 20–70% MeCN containing 0.1% TFA over 50 min. The LC-ESI-MS analysis was performed on an Exactive Plus Orbitrap mass spectrometer.
Figure 2
Figure 2
Comparison of the antisera binding to the envelope glycoprotein gp120s and gp140s derived from different HIV-1 strains. (a) HIV-1 CN54, (b) HIV-1 CON-S, (c) HIV-1 JR-CSF, (d) HIV-1 A244, (e) HIV-1 JR-FL, (f) HIV-1 SF162, and (g) the alignment of the V3 domain sequences derived from different HIV-1 strains. The numbering is based on the HBX2 strain; the gp is the sequence of the designed synthetic glycopeptide where the highly variable tip was deleted to avoid dominant strain-specific immune response. The CN54, CON-S, and JR-CSF gp120s and JR-FL and SF162 gp140s all have a conserved N-glycan at the N332 site, while the N332 glycosylation site was shifted to N334 in the A244 gp120.
Figure 3
Figure 3
ELISA binding to the synthetic V3 glycopeptides. (a) Structure of the V3 peptide and glycopeptides used for ELISA analysis. (b) Binding of the pretreated antisera induced by the three-component immunogen 1 to the V3 peptides and glycopeptides. (c) Binding of pretreated antisera induced by three-component trivalent immunogen 4 to the V3 peptide (5), glycopeptides (6–8), and trivalent glycan cluster (9). (d) Binding of the antisera and pretreated antisera induced by immunogen 1 to monovalent glycopeptide 6. (e) Antisera and pretreated antisera induced by immunogen 4 to trivalent glycopeptide 8.
See this image and copyright information in PMC

References

    1. Julien J. P.; Cupo A.; Sok D.; Stanfield R. L.; Lyumkis D.; Deller M. C.; Klasse P. J.; Burton D. R.; Sanders R. W.; Moore J. P.; Ward A. B.; Wilson I. A. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science 2013, 342, 1477–1483. 10.1126/science.1245625. - DOI - PMC - PubMed
    1. Haynes B. F.; Burton D. R. Developing an HIV vaccine. Science 2017, 355, 1129–1130. 10.1126/science.aan0662. - DOI - PMC - PubMed
    1. Stewart-Jones G. B.; Soto C.; Lemmin T.; Chuang G. Y.; Druz A.; Kong R.; Thomas P. V.; Wagh K.; Zhou T.; Behrens A. J.; Bylund T.; Choi C. W.; Davison J. R.; Georgiev I. S.; Joyce M. G.; Kwon Y. D.; Pancera M.; Taft J.; Yang Y.; Zhang B.; Shivatare S. S.; Shivatare V. S.; Lee C. C.; Wu C. Y.; Bewley C. A.; Burton D. R.; Koff W. C.; Connors M.; Crispin M.; Baxa U.; Korber B. T.; Wong C. H.; Mascola J. R.; Kwong P. D. Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G. Cell 2016, 165, 813–826. 10.1016/j.cell.2016.04.010. - DOI - PMC - PubMed
    1. Pancera M.; Zhou T.; Druz A.; Georgiev I. S.; Soto C.; Gorman J.; Huang J.; Acharya P.; Chuang G. Y.; Ofek G.; Stewart-Jones G. B.; Stuckey J.; Bailer R. T.; Joyce M. G.; Louder M. K.; Tumba N.; Yang Y.; Zhang B.; Cohen M. S.; Haynes B. F.; Mascola J. R.; Morris L.; Munro J. B.; Blanchard S. C.; Mothes W.; Connors M.; Kwong P. D. Structure and immune recognition of trimeric pre-fusion HIV-1 Env. Nature 2014, 514, 455–461. 10.1038/nature13808. - DOI - PMC - PubMed
    1. Horiya S.; MacPherson I. S.; Krauss I. J. Recent strategies targeting HIV glycans in vaccine design. Nat. Chem. Biol. 2014, 10, 990–999. 10.1038/nchembio.1685. - DOI - PMC - PubMed

LinkOut - more resources