Selective recognition of oligomeric HIV-1 primary isolate envelope glycoprotelins by potently neutralizing ligands requires efficient precursor cleavage
Selective recognition of oligomeric HIV-1 primary isolate envelope glycoprotelins by potently neutralizing ligands requires efficient precursor cleavage
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DOI：
10.1016/j.virol.2004.10.042
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发表时间：
2005-02-05
期刊：
影响因子：
3.7
通讯作者：
Wyatt, R
中科院分区：
文献类型：
--
作者：
Pancera, M;Wyatt, R
有效的艾滋病毒疫苗的一个关键组成部分将是诱导广泛的中和抗体。由HIV尖峰、外膜糖蛋白gp120和跨膜糖蛋白gp41组成，介导受体结合、病毒侵入，并是中和抗体的靶标。Gp120和gp41糖蛋白来源于gp160前体糖蛋白，在gp160糖基化、内质网和高尔基体内寡聚和裂解后，仍然是异源二聚体的非共价结合三聚体。以前，使用来自实验室适应的HIV-1毒株感染的细胞表面包膜糖蛋白，已经建立了gp120定向抗体与病毒糖蛋白的结合和抗体中和实验室适应分离株的能力之间的相关性。然而，对于来自原发患者分离株的糖蛋白来说，这一点更难证明。在这里，使用基于FACS的方法，我们报告只有gp120指导的中和抗体和中和配体可溶性CD4有效地与来自JR-FL初级分离物的糖蛋白结合，前提是gp160前体蛋白被有效切割。细胞表面生物素化和Western blotting显示前体被切割。与之形成鲜明对比的是，非中和抗体和中和抗体都能结合来自JR-FL和YU2分离株的未切割的包膜糖蛋白。这些数据表明，环境蛋白尖峰结构的显着变化取决于前体gp160的切割，并与限制结合环境蛋白的中和模型一致。这些数据还涉及到使用和设计非裂解包膜糖蛋白三聚体免疫原作为一种手段来选择性和优先地向宿主免疫系统呈递中和表位。由爱思唯尔公司出版。
A critical component of an effective HIV vaccine will be the induction of broadly neutralizing antibodies. Comprising the HIV spike, the exterior envelope glycoprotein gp120 and the transmembrane glycoprotein gp41 mediate receptor binding, viral entry, and are the targets for neutralizing antibodies. The gp120 and gp41 glycoproteins are derived from the gp160 precursor glycoprotein and following gp160 glycosylation, oligomerization and cleavage in the endoplasmic reticulum and Golgi, remain as non-covalently associated trimers of heterodimers. Previously, using cell-surface envelope glycoproteins derived from infection of a laboratory-adapted HIV-1 strain, a correlation had been established between the binding of gp120-directed antibodies to the viral glycoprotein and the ability of the antibodies to neutralize laboratory-adapted isolates. However, this has been more difficult to demonstrate for glycoproteins derived from primary patient isolates. Here, using a FACS-based method, we report that only gp120-directed neutralizing antibodies and the neutralizing ligand soluble CD4 efficiently bind to glycoproteins derived from the JR-FL primary isolate provided that the gp160 precursor protein is efficiently cleaved. Precursor cleavage was demonstrated by cell-surface biotinylation and Western blotting. In stark contrast, both non-neutralizing and neutralizing antibodies bind non-cleaved envelope glycoproteins from JR-FL and YU2 isolates. These data imply that significant changes in Env spike structure are dependent upon precursor gp160 cleavage and are consistent with a restricted-binding-to-Env model of neutralization. The data also have implications in regards to the use and design of non-cleaved envelope glycoprotein trimeric immunogens as a means to selectively and preferentially present neutralizing epitopes to the host immune system. Published by Elsevier Inc.