Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline
Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline
复制标题
DOI：
10.1016/s0002-9440(10)64304-0
复制
发表时间：
2003-05-01
影响因子：
6
通讯作者：
He, JJ
中科院分区：
文献类型：
--
作者：
Kim, BO;Liu, Y;He, JJ
人类免疫缺陷病毒1型（HIV-1）达特蛋白是多种获得性免疫缺陷综合征（AIDS）相关疾病的关键致病因子。许多研究已经证明了达特蛋白的神经毒性性质，因此，达特被认为与艾滋病相关的神经系统疾病有关。然而，这些研究中的大部分是在体外神经元培养中进行的，而没有考虑脑中复杂的细胞-细胞相互作用，或者通过将重组达特蛋白注射到脑中进行的，这可能对脑造成继发性应激或损伤。为了更好地了解达特蛋白在HIV-1神经发病机制中的作用，我们试图建立一种转基因小鼠模型，其中达特蛋白的表达受到星形胶质细胞特异性胶质纤维酸性蛋白启动子和强力霉素（Dox）诱导型启动子的调节。在本研究中，我们的特点是这些小鼠的表型和神经病理学特征。体外和体内试验均证实，达特表达仅发生在星形胶质细胞中，并且是Dox依赖性的。脑中的达特表达导致发育障碍、驼背、震颤、共济失调、认知和运动缓慢、癫痫发作和过早死亡。这些小鼠的神经病理学特征为小脑和皮质的破坏、脑水肿、星形细胞增多、神经元树突变性、神经元凋亡以及活化的单核细胞和T淋巴细胞浸润增加。这些结果共同表明，在没有HIV-1感染的情况下，达特表达足以引起与AIDS患者脑中所注意到的大多数神经病理学相似的神经病理学，并提供了在整个生物体背景下支持达特蛋白在HIV-1神经发病机制中的关键作用的第一个证据。更重要的是，我们的数据表明，Dox诱导的，脑靶向达特转基因小鼠提供了一个体内模型，描绘的达特神经毒性的分子机制，并制定治疗策略，治疗艾滋病毒相关的神经系统疾病。
The human immunodeficiency virus type 1 (HIV-1) Tat protein is a key pathogenic factor in a variety of acquired immune deficiency syndrome (AIDS)-associated disorders. A number of studies have documented the neurotoxic property of Tat protein, and Tat has therefore been proposed to contribute to AIDS-associated neurological diseases. Nevertheless, the bulk of these studies are performed in in vitro neuronal cultures without taking into account the intricate cell-cell interaction in the brain, or by injection of recombinant Tat protein into the brain, which may cause secondary stress or damage to the brain. To gain a better understanding of the roles of Tat protein in HIV-1 neuropathogenesis, we attempted to establish a transgenic mouse model in which Tat expression was regulated by both the astrocyte-specific glial fibrillary acidic protein promoter and a doxycycfne (Dox)inducible promoter. In the present study, we characterized the phenotypic and neuropathogenic features of these mice. Both in vitro and in vivo assays confirmed that Tat expression occurred exclusively in astrocytes and was Dox-dependent. Tat expression in the brain caused failure to thrive, hunched gesture, tremor, ataxia, and slow cognitive and motor movement, seizures, and premature death. Neuropathologies of these mice were characterized by breakdown of cerebellum and cortex, brain edema, astrocytosis, degeneration of neuronal dendrites, neuronal apoptosis, and increased infiltration of activated monocytes and T lymphocytes. These results together demonstrate that Tat expression in the absence of HIV-1 infection is sufficient to cause neuropathologies similar to most of those noted in the brain of AIDS patients, and provide the first evidence in the context of a whole organism to support a critical role of Tat protein in HIV-1 neuropathogenesis. More importantly, our data suggest that the Dox inducible, brain-targeted Tat transgenic mice offer an in vivo model for delineating the molecular mechanisms of Tat neurotoxicity and for developing therapeutic strategies for treating HIV-associated neurological disorders.