Enhanced Human Immunodeficiency Virus Type 1 Expression and Neuropathogenesis in Knockout Mice Lacking Type I Interferon Responses
Enhanced Human Immunodeficiency Virus Type 1 Expression and Neuropathogenesis in Knockout Mice Lacking Type I Interferon Responses
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DOI：
10.1097/nen.0000000000000026
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发表时间：
2014-01-01
影响因子：
3.2
通讯作者：
Volsky, David J.
中科院分区：
文献类型：
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作者：
He, Hongxia;Sharer, Leroy R.;Volsky, David J.
I型干扰素在人类免疫缺陷病毒1型(HIV-1)神经发病机制中的作用尚不清楚；干扰素信号既有保护作用，也有有害作用。我们利用缺乏I型干扰素受体的转基因小鼠(IFNRKO)来分析在缺乏干扰素信号的情况下HIV-1脑感染和神经发病的进展。在129xSv/EV或C57BL/6毒株背景上的IFNRKO和野生型(WT)小鼠被系统感染EcoHIV，一种能有效感染小鼠的嵌合HIV-1。与WT小鼠相比，IFNRKO小鼠在脾和腹膜巨噬细胞中表现出更高的HIV-1表达，并且病毒更多地渗透到大脑中。立体定向脑内注射病毒后，通过组织病理学、免疫组织化学、免疫荧光和聚合酶链式反应等方法研究病毒脑内感染后的神经发病机制。IFNRKO和WT小鼠都显示出容易检测到的HIV-1和脑损伤，包括小胶质细胞激活、星形胶质细胞增多，以及人类HIV-1脑部疾病典型的炎性细胞因子和趋化因子编码基因的表达增加。IFNRKO小鼠的HIV-1神经致病参数，包括小胶质细胞/巨噬细胞中HIV-1的表达，显著高于WT小鼠。我们的结果明确地表明，I型干扰素信号和反应限制了HIV-1在小鼠大脑中的感染和发病。
The roles of Type I interferon (IFN) in human immunodeficiency virus Type 1 (HIV-1) neuropathogenesis are poorly understood; both protective and deleterious effects of IFN signaling have been described. We used genetically modified mice deficient in the Type I IFN receptor (IFNRKO) to analyze the progress of HIV-1 brain infection and neuropathogenesis in the absence of IFN signaling. IFNRKO and wild-type (WT) mice on the 129xSv/Ev or C57BL/6 strain backgrounds were infected systemically with EcoHIV, a chimeric HIV-1 that productively infects mice. IFNRKO mice showed higher HIV-1 expression in spleen and peritoneal macrophages and greater virus infiltration into the brain compared to WT mice. Neuropathogenesis was studied by histopathological, immunohistochemical, immunofluorescence, and polymerase chain reaction analyses of brain tissues after the virus was inoculated into the brain by stereotaxic intracerebral injection. Both IFNRKO and WT mice showed readily detectable HIV-1 and brain lesions, including microglial activation, astrocytosis, and increased expression of genes coding for inflammatory cytokines and chemokines typical of human HIV-1 brain disease. Parameters of HIV-1 neuropathogenesis, including HIV-1 expression in microglia/macrophages, were significantly greater in IFNRKO than in WT mice. Our results show unequivocally that Type I IFN signaling and responses limit HIV-1 infection and pathogenesis in the brains of mice.