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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection
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The brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection

机译：脑特异性因子FEZ1是神经元对HIV-1感染的易感性的决定因素

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摘要

Neurons are one of the few cell types in the human body that do not support HIV type-1 (HIV-1) replication. Although the lack of key receptors is a major obstacle to infection, studies suggest that additional functions inhibit virus replication to explain the exquisite resistance of neurons to HIV-1. However, specific neuronal factors that may explain this resistance remain to be discovered. In a screen for antiviral factors using a fibroblast line chemically mutagenized and selected for resistance to retroviral infection, we recently identified induction of rat FEZ1 (fasciculation and elongation protein zeta-1), a brain-specific protein, as the cause of this resistance. When exogenously expressed in nonneuronal cell lines rat FEZ1 blocked nuclear entry of retroviral DNA. Here, we demonstrate that among human brain cells, neurons naturally express high levels of FEZ1 compared to astrocytes or microglia cells and are correspondingly less susceptible to infection with pseudotyped HIV-1 that bypasses receptor-mediated viral entry. Demonstrating that endogenous FEZ1 was functionally important in the resistance of neurons to HIV-1 infection, siRNA-mediated knockdown of endogenous FEZ1 increased the infectivity of neurons while sensitive brain cell types like microglia became more resistant upon FEZ1 overexpression. In addition, FEZ1 expression was not induced in response to IFN treatment. As such, in contrast to other widely expressed, IFN-inducible antiviral factors, FEZ1 appears to represent a unique neuron-specific determinant of cellular susceptibility to infection in a cell type that is naturally resistant to HIV-1.
机译：神经元是人体中少数不支持HIV 1型（HIV-1）复制的细胞类型之一。尽管关键受体的缺乏是感染的主要障碍，但研究表明，其他功能可以抑制病毒复制，从而说明神经元对HIV-1的抵抗力。然而，仍然可以发现可以解释这种抗性的特定神经元因子。在使用化学诱变并选择对逆转录病毒感染具有抗性的成纤维细胞系筛选抗病毒因子的过程中，我们最近确定了诱导大鼠FEZ1（束缚和延伸蛋白zeta-1）（一种大脑特异性蛋白）的原因是这种抗性的原因。当在非神经元细胞系中外源表达时，大鼠FEZ1会阻止逆转录病毒DNA的核进入。在这里，我们证明了在人类脑细胞中，与星形胶质细胞或小胶质细胞相比，神经元自然表达高水平的FEZ1，并且相应地更不容易受到绕过受体介导的病毒进入的假型HIV-1的感染。证明内源性FEZ1在神经元对HIV-1感染的抵抗中功能上很重要，siRNA介导的内源性FEZ1的敲低增加了神经元的感染性，而敏感的脑细胞类型（如小胶质细胞）对FEZ1的过度表达更具抵抗力。另外，未响应于IFN处理而诱导FEZ1表达。因此，与其他广泛表达的，IFN诱导的抗病毒因子相反，FEZ1似乎代表了在自然抵抗HIV-1的细胞类型中细胞对感染的易感性的独特神经元特异性决定因素。

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    Juliane Haedicke; Craig Brown; Mojgan H. Naghavi;

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    Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland;

    Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland;

    Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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