Biophysical characterization of gp41 aggregates suggests a model for the molecular mechanism of HIV-associated neurological damage and dementia
Biophysical characterization of gp41 aggregates suggests a model for the molecular mechanism of HIV-associated neurological damage and dementia
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DOI：
10.1074/jbc.m001036200
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发表时间：
2000-06-30
影响因子：
4.8
通讯作者：
Clore, GM
中科院分区：
文献类型：
--
作者：
Caffrey, M;Braddock, DT;Clore, GM
在人类免疫缺陷病毒（HIV）感染的个体中，脑组织中HIV包膜蛋白gp 41的水平与神经损伤和痴呆相关，本文通过生物化学方法和电子显微镜观察，证明了纯化的HIV和猴免疫缺陷病毒gp 41（e-gp 41）的胞外结构域在生理pH下形成可溶性高分子量聚集体和天然三聚体的混合物。显示e-gp 41聚集体主要是α-螺旋的并且对变性剂相对稳定，高分子量形式的e-gp 41的大小在7至70个三聚体范围内可变，其通过在聚集体内部的相互作用缔合，所述聚集体涉及连接e-gp 41核心的N-和C-末端螺旋的环。三聚体主要以其长轴径向取向排列，并且高分子量聚集体的宽度对应于两个e-gp 41三聚体的长度（类似于200埃）。使用光镜和电镜结合免疫组化，我们发现，HIV gp 41积累作为一种细胞外聚集体在诊断为痴呆的HIV感染患者的大脑中，我们推测，高分子量聚集体的e-gp 41负责HIV相关的神经损伤和痴呆，符合已知的机制脑病。
In human immunodeficiency virus (HIV)-infected individuals, the level of the HIV envelope protein gp41 in brain tissue is correlated with neurological damage and dementia, In this paper we show by biochemical methods and electron microscopy that the extracellular ectodomain of purified HIV and simian immunodeficiency virus gp41 (e-gp41) forms a mixture of soluble high molecular weight aggregate and native trimer at physiological pH. The e-gp41 aggregate is shown to be largely alpha-helical and relatively stable to denaturants, The high molecular weight form of e-gp41 is variable in size ranging from 7 to 70 trimers, which associate by interactions at the interior of the aggregate involving the loop that connects the N- and C-terminal helices of the e-gp41 core. The trimers are predominantly arranged with their long axes oriented radially, and the width of the high molecular weight aggregate corresponds to the length of two e-gp41 trimers (similar to 200 Angstrom). Using both light and electron microscopy combined with immunohistochemistry we show that HIV gp41 accumulates as an extracellular aggregate in the brains of HIV-infected patients diagnosed with dementia, We postulate that the high molecular weight aggregates of e-gp41 are responsible for HIV-associated neurological damage and dementia, consistent with known mechanisms of encephalopathy.