High-Density Array of Well-Ordered HIV-1 Spikes on Synthetic Liposomal Nanoparticles Efficiently Activate B Cells.
High-Density Array of Well-Ordered HIV-1 Spikes on Synthetic Liposomal Nanoparticles Efficiently Activate B Cells.
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DOI：
10.1016/j.celrep.2016.04.078
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发表时间：
2016-05-31
期刊：
影响因子：
8.8
通讯作者：
Wyatt RT
中科院分区：
文献类型：
--
作者：
Ingale J;Stano A;Guenaga J;Sharma SK;Nemazee D;Zwick MB;Wyatt RT
研制HIV-1疫苗的一个主要步骤是研制出能够诱导中和抗体的免疫原。包膜糖蛋白（Env）。模拟物，如NFL和SOSIP设计，产生天然样的、有序的三聚体，并引发第2层同源中和（SOSIP）。我们推断，与可溶性三聚体相比，通过高密度颗粒阵列显示良好有序的三聚体将增加B细胞活化。在这里，我们提出了脂质体纳米粒子的设计，在其表面上显示良好有序的Env穗三聚体。生物物理分析，冷冻和负染色电子显微镜和广泛中和抗体的面板结合分析确认高密度，有序的三聚体颗粒阵列。与可溶性三聚体相比，Env三聚体缀合的脂质体在体外激活B细胞和体内激活生殖中心B细胞方面具有上级优势。此外，三聚体缀合的脂质体引起适度的2级同源中和抗体。三聚体缀合的脂质体代表了朝向开发更有效的HIV疫苗免疫原的有希望的初始引导。Ingale等人在合成脂质体表面以高密度排列有序的HIV包膜糖蛋白（Env）三聚体。三聚体-脂质体是均质的，并且被针对HIV-1的广泛中和抗体充分识别。高密度颗粒三聚体阵列更有效地离体活化Env特异性B细胞，增强体内生发中心B细胞的产生。
A major step towards an HIV-1 vaccine is an immunogen capable of inducing neutralizing antibodies. Envelope glycoprotein (Env). mimetics, such as the NFL and SOSIP designs, generate native-like, well-ordered trimers and elicit tier 2 homologous neutralization (SOSIPs). We reasoned that the display of well-ordered trimers by high-density, particulate array would increase B cell activation compared to soluble trimers. Here, we present the design of liposomal nanoparticles displaying well-ordered Env spike trimers on their surface. Biophysical analysis, cryo- and negative-stain electron microscopy and binding analysis with a panel of broadly neutralizing antibodies confirm high-density, well-ordered trimer particulate array. The Env trimer-conjugated liposomes were superior to soluble trimers in activating B cells ex vivo and germinal center B cells in vivo. In addition, the trimer-conjugated liposomes elicited modest tier 2 homologous neutralizing antibodies. The trimer-conjugated liposomes represent a promising initial lead towards the development of more effective HIV vaccine immunogens. Ingale et al array well-ordered HIV envelope glycoprotein (Env) trimers at high density on the surface of synthetic liposomes. The trimer-liposomes are homogenous, and well recognized by broadly neutralizing antibodies against HIV-1. High-density particulate trimer array more efficiently activates Env-specific B cells ex vivo, enhancing the generation of germinal center B cells in vivo.