HIV-1 Nef expression in microglia disrupts dopaminergic and immune functions with associated mania-like behaviors
HIV-1 Nef expression in microglia disrupts dopaminergic and immune functions with associated mania-like behaviors
复制标题
DOI：
10.1016/j.bbi.2014.02.016
复制
发表时间：
2014-08-01
影响因子：
15.1
通讯作者：
Power, Christopher
中科院分区：
文献类型：
--
作者：
Acharjee, Shaona;Branton, William G.;Power, Christopher
背景：HIV/AIDS期间的神经精神障碍是常见的，尽管脑内HIV-1感染，特别是单个HIV-1蛋白对这些大脑疾病的发展的贡献尚不清楚。本研究建立了在小胶质细胞中表达HIV-1Nef蛋白的体内转基因小鼠模型，为研究神经行为表型及其相关的细胞和分子特性奠定了基础。方法：对c-fms启动子控制下表达全长HIV-1nef的转基因(TG)小鼠和野生型(Wt)小鼠进行了不同的神经行为测试，包括运动、强迫游泳(FST)、高架+迷宫(EPM)和T迷宫测试。用RT-PCR、免疫印迹、酶活性和免疫组织化学方法检测宿主基因和转基因的表达。结果：TG动物脑内小胶质细胞和培养的巨噬细胞均有Nef的表达。与Wt胎仔相比，Tg雄鼠表现出多动行为，包括增加运动活动，减少FST中的不动，增加张开手臂的EPM探索(p<；0.05)。与Wt组相比，Tg组大鼠纹状体内CCL2表达增加，同时干扰素-α受到抑制(p<；0.05)。TG动物纹状体内多巴胺水平、MAO活性和多巴胺转运体(DAT)表达降低(p<；0.05)。结论：HIV-1Nef在小胶质细胞中的表达诱导了CCL2的表达，并扰乱了纹状体多巴胺能传递，导致了在HIV感染者中出现的躁狂症和其他精神共病的多动行为。这些发现强调了大脑中单个病毒蛋白的选择性效应及其参与神经发病机制。(C)2014年，爱思唯尔公司出版。
Background: Neuropsychiatric disorders during HIV/AIDS are common although the contribution of HIV-1 infection within the brain, and in particular individual HIV-1 proteins, to the development of these brain disorders is unknown. Herein, an in vivo transgenic mouse model was generated in which the HIV-1 Nef protein was expressed in microglia cells, permitting investigation of neurobehavioral phenotypes and associated cellular and molecular properties.Methods: Transgenic (Tg) mice that expressed full length HIV-1 nef under the control of the c-fms promoter and wildtype (Wt) littermates were investigated using different measures of neurobehavioral performance including locomotory, forced swim (FST), elevated plus maze (EPM) and T-maze tests. Host gene and transgene expression were assessed by RT-PCR, immunoblotting, enzymatic activity and immunohistochemistry. Biogenic amine levels were measured by HPLC with electrochemical detection.Results: Tg animals exhibited Nef expression in brain microglia and cultured macrophages. Tg males displayed hyperactive behaviors including augmented locomotor activity, decreased immobility in the FST and increased open-arm EPM exploration compared to Wt littermates (p < 0.05). Tg animals showed increased CCL2 expression with concurrent IFN-alpha suppression in striatum compared with Wt littermates (p < 0.05). Dopamine levels, MAO activity and the dopamine transporter (DAT) expression were reduced in the striatum of Tg animals (p < 0.05).Conclusions: HIV-1 Nef expression in microglia induced CCL2 expression together with disrupting striatal dopaminergic transmission, resulting in hyperactive behaviors which are observed in mania and other psychiatric comorbidities among HIV-infected persons. These findings emphasize the selective effects of individual viral proteins in the brain and their participation in neuropathogenesis. (C) 2014 Published by Elsevier Inc.