Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers.
Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers.
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DOI：
10.1016/j.celrep.2015.05.017
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发表时间：
2015-06-16
期刊：
影响因子：
8.8
通讯作者：
Crispin M
中科院分区：
文献类型：
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作者：
Pritchard LK;Vasiljevic S;Ozorowski G;Seabright GE;Cupo A;Ringe R;Kim HJ;Sanders RW;Doores KJ;Burton DR;Wilson IA;Ward AB;Moore JP;Crispin M
高度糖基化的三聚体包膜糖蛋白（Env）介导HIV-1进入细胞。聚糖的高密度和异质性保护Env不被免疫系统识别，但矛盾的是，许多有效的广泛中和抗体（bNAb）识别涉及该聚糖屏蔽的表位。为了更好地理解Env糖基化及其在bNAb识别中的作用，我们表征了可溶性切割的重组三聚体（BG 505 SOSIP.664），其是天然Env的接近结构和抗原模拟物。大的，未加工的寡甘露糖型结构（Man 8 - 9 GlcNAc 2）是显着普遍的三聚体的gp 120组件，无论哺乳动物细胞表达系统或用于亲和纯化的bNAb。相比之下，gp 41亚基携带更高度加工的聚糖。未切割的非天然寡聚gp 140蛋白上的聚糖也被高度加工。因此，同质的寡甘露糖主导的聚糖谱是天然Env构象的标志，也是可用于bNAb识别和疫苗设计的潜在阿基里斯之踵。
A highly glycosylated, trimeric envelope glycoprotein (Env) mediates HIV-1 cell entry. The high density and heterogeneity of the glycans shield Env from recognition by the immune system but, paradoxically, many potent broadly neutralizing antibodies (bNAbs) recognize epitopes involving this glycan shield. To better understand Env glycosylation and its role in bNAb recognition, we characterized a soluble, cleaved recombinant trimer (BG505 SOSIP.664) that is a close structural and antigenic mimic of native Env. Large, unprocessed oligomannose-type structures (Man8-9GlcNAc2) are notably prevalent on the gp120 components of the trimer, irrespective of the mammalian cell expression system or the bNAb used for affinity-purification. In contrast, gp41 subunits carry more highly processed glycans. The glycans on uncleaved, non-native oligomeric gp140 proteins are also highly processed. A homogeneous, oligomannose-dominated glycan profile is therefore a hallmark of a native Env conformation and a potential Achilles’ heel that can be exploited for bNAb recognition and vaccine design.