Integrity of Glycosylation Processing of a Glycan-Depleted Trimeric HIV-1 Immunogen Targeting Key B-Cell Lineages,Journal of Proteome Research

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Integrity of Glycosylation Processing of a Glycan-Depleted Trimeric HIV-1 Immunogen Targeting Key B-Cell Lineages
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2018-02-08 00:00:00 , DOI: 10.1021/acs.jproteome.7b00639
Anna-Janina Behrens ₁ , Abhinav Kumar ₁ , Max Medina-Ramirez ₂ , Albert Cupo ₃ , Kevin Marshall ₃ , Victor M Cruz Portillo ₃ , David J Harvey ₁ , Gabriel Ozorowski ₄ , Nicole Zitzmann ₁ , Ian A Wilson _{4,

5} , Andrew B Ward ₄ , Weston B Struwe ₁ , John P Moore ₃ , Rogier W Sanders _{2,

3} , Max Crispin _{1,

6}

Affiliation

Broadly neutralizing antibodies (bNAbs) that target the trimeric HIV-1 envelope glycoprotein spike (Env) are tools that can guide the design of recombinant Env proteins intended to engage the predicted human germline precursors of bNAbs (gl-bNAbs). The protein components of gl-bNAb epitopes are often masked by glycans, while mature bNAbs can evolve to accommodate or bypass these shielding glycans. The design of germline-targeting Env immunogens therefore includes the targeted deletion of specific glycan sites. However, the processing of glycans on Env trimers can be influenced by the density with which they are packed together, a highly relevant point given the essential contributions under-processed glycans make to multiple bNAb epitopes. We sought to determine the impact of the removal of 15 potential N-glycan sites (5 per protomer) from the germline-targeting soluble trimer, BG505 SOSIP.v4.1-GT1, using quantitative, site-specific N-glycan mass spectrometry analysis. We find that, compared with SOSIP.664, there was little overall change in the glycan profile but only subtle increases in the extent of processing at sites immediately adjacent to where glycans had been deleted. We conclude that multiple glycans can be deleted from BG505 SOSIP trimers without perturbing the overall integrity of the glycan shield.

中文翻译：

针对关键 B 细胞谱系的去聚糖三聚体 HIV-1 免疫原的糖基化过程的完整性

针对三聚体 HIV-1 包膜糖蛋白尖峰 (Env) 的广泛中和抗体 (bNAb) 是可以指导重组 Env 蛋白设计的工具，这些蛋白旨在与预测的人类生殖系 bNAb (gl-bNAb) 前体结合。gl-bNAb 表位的蛋白质成分通常被聚糖掩盖，而成熟的 bNAb 可以进化以适应或绕过这些屏蔽聚糖。因此，针对种系的 Env 免疫原的设计包括特定聚糖位点的靶向缺失。然而，Env 三聚体上聚糖的加工可能会受到它们包装在一起的密度的影响，考虑到加工不足的聚糖对多个 bNAb 表位的重要贡献，这是一个高度相关的点。我们试图使用定量、位点特异性 N-聚糖质谱分析来确定从种系靶向可溶性三聚体 BG505 SOSIP.v4.1-GT1 中去除 15 个潜在 N-聚糖位点（每个原聚体 5 个）的影响. 我们发现，与 SOSIP.664 相比，聚糖谱的整体变化很小，但在紧邻聚糖被删除的位置处加工程度仅略有增加。我们得出结论，可以从 BG505 SOSIP 三聚体中删除多个聚糖，而不会干扰聚糖屏蔽的整体完整性。聚糖谱几乎没有整体变化，但在聚糖被删除的紧邻位点的加工程度仅略有增加。我们得出结论，可以从 BG505 SOSIP 三聚体中删除多个聚糖，而不会干扰聚糖屏蔽的整体完整性。聚糖谱几乎没有整体变化，但在聚糖被删除的紧邻位点的加工程度仅略有增加。我们得出结论，可以从 BG505 SOSIP 三聚体中删除多个聚糖，而不会干扰聚糖屏蔽的整体完整性。

更新日期：2018-02-09

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