Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, California 92037, USA.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Nat Commun. 2016 Jun 28;7:12041. doi: 10.1038/ncomms12041.
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.
BG505 SOSIP.664 三聚体与广泛中和抗体（bNAb）复合物的结构揭示了三聚体结构对于 HIV-1 免疫识别的关键作用。因此，在纳米颗粒上展示三聚体 HIV-1 抗原可能提供有前途的疫苗候选物。在这里，我们报告了 HIV-1 三聚体呈递纳米颗粒的合理设计、结构分析和抗原评估。我们首先证明 V1V2 和 gp120 都可以在纳米颗粒上以天然三聚体构象呈现。然后，我们设计了基于铁蛋白和展示 20 个模拟病毒样颗粒（VLPs）的 60 聚体 E2p 的各种形式稳定的 gp140 三聚体呈现的纳米颗粒。通过电子显微镜（EM）确认颗粒组装，同时使用代表性的 bNAb 和非 bNAb 生成抗原谱。最后，我们证明了高产量的 gp140 纳米颗粒的生产以及 gp120 和 gp140 纳米颗粒对携带同源 VRC01 受体的 B 细胞的强烈刺激。总之，我们的研究为 HIV-1 疫苗的开发提供了多种多价免疫原。
