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Nat Commun. 2016 Jun 28;7:12041. doi: 10.1038/ncomms12041.

Presenting native-like trimeric HIV-1 antigens with self-assembling nanoparticles.

He L1, de Val N2,3,4, Morris CD1, Vora N1, Thinnes TC1, Kong L2,3,4, Azadnia P1, Sok D1,3,4, Zhou B5, Burton DR1,3,4,6, Wilson IA2,3,4,7,8, Nemazee D1, Ward AB2,3,4, Zhu J1,2,4.

Author information

1
Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, California 92037, USA.
2
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
3
International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
4
Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
5
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
6
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02139-3583, USA.
7
The Joint Center for Structural Genomics, The Scripps Research Institute, La Jolla, California 92037, USA.
8
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

Abstract

Structures of BG505 SOSIP.664 trimer in complex with broadly neutralizing antibodies (bNAbs) have revealed the critical role of trimeric context for immune recognition of HIV-1. Presentation of trimeric HIV-1 antigens on nanoparticles may thus provide promising vaccine candidates. Here we report the rational design, structural analysis and antigenic evaluation of HIV-1 trimer-presenting nanoparticles. We first demonstrate that both V1V2 and gp120 can be presented in native-like trimeric conformations on nanoparticles. We then design nanoparticles presenting various forms of stabilized gp140 trimer based on ferritin and a large, 60-meric E2p that displays 20 spikes mimicking virus-like particles (VLPs). Particle assembly is confirmed by electron microscopy (EM), while antigenic profiles are generated using representative bNAbs and non-NAbs. Lastly, we demonstrate high-yield gp140 nanoparticle production and robust stimulation of B cells carrying cognate VRC01 receptors by gp120 and gp140 nanoparticles. Together, our study provides an arsenal of multivalent immunogens for HIV-1 vaccine development.

PMID:
27349934
PMCID:
PMC4931238
DOI:
10.1038/ncomms12041
[Indexed for MEDLINE]
Free PMC Article

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