Mechanisms involved in HIV-1 Tat mediated neuronal damage

描述（由申请人提供）：目前，超过4000万人感染HIV-1，艾滋病是全球第四大死亡原因。高效抗逆转录病毒疗法的采用大大降低了艾滋病毒介导的免疫抑制和死亡率。然而，它可能无法预防与HIV-1感染相关的神经元损伤，随着艾滋病患者寿命的延长，对中枢神经系统的进行性损伤可能是一个新出现的问题。在已显示促进神经元毒性的因素中，病毒调节蛋白达特引起了特别的关注。达特蛋白由HIV-1感染的宿主细胞分泌，并已显示进入旁观者未感染的细胞，包括神经元。最近，我们已经确定了一个新的机制，其中达特可以诱导神经元损伤。它涉及达特与微管蛋白的结合，泛素-蛋白酶体系统向微管附近的募集，以及微管相关蛋白2（MAP 2）（细胞骨架的关键组分）的降解。HIV-1脑病（HIVE）脑组织的临床样本的免疫组织化学分析表明，达特主要存在于小胶质细胞结节附近的神经元细胞质中，并在70%的受影响的神经元细胞的MAP 2的损失。观察到达特可以解除对细胞骨架因子的调节，这使我们假设依赖于细胞骨架完整性的分子事件，如RNA运输也可能受损。我们的初步数据证实了达特改变一组小RNA（称为微小RNA）表达的能力，这些小RNA是已知的翻译抑制因子。在这些结果的基础上，我们将测试的假设，即在神经元中，达特可以改变蛋白质的合成，通过调节细胞骨架的活性，蛋白酶体和表达的microRNA翻译抑制剂。我们希望这项研究的结果将重新定义我们对Tat介导的神经毒性的认识，并为更有效的治疗干预提供潜在的靶点。

DESCRIPTION (provided by applicant): Presently, more than 40 millions people are infected with HIV-1, and AIDS is the fourth leading cause of death worldwide. The introduction of highly active antiretroviral therapy (HAART) has greatly reduced HIV-mediated immunosuppression and mortality. However, it may not prevent neuronal damage associated with HIV-1 infection, and progressive damage to the Central Nervous System may be an emerging problem as AIDS patients live longer. Among the factors that have been shown to promote neuronal toxicity, the viral regulatory protein Tat has captured special attention. Tat protein is secreted by HIV-1 infected host cells and has been shown to enter bystander non-infected cells, including neurons. Recently, we have identified a new mechanism by which Tat can induce neuronal damage. It involves the binding of Tat to tubulin, recruitment of the ubiquitin-proteasome system to the proximity of microtubules, and degradation of microtubule-associated protein 2 (MAP2), a critical component of the cytoskeleton. Immunohistochemical analysis of clinical samples from HIV-1 encephalopathy (HIVE) brain tissues demonstrated a predominantly cytoplasmic presence of Tat in neurons near microglial nodules, and loss of MAP2 in 70% of the affected neuronal cells. The observation that Tat can deregulate cytoskeletal factors led us to hypothesize that molecular events that depend on cytoskeletal integrity such as RNA trafficking could be also impaired. Our preliminary data confirm the ability of Tat to alter the expression of a subset of small RNAs, called microRNAs, which are known translational repressers. On the basis of these results, we will test the hypothesis that in neurons Tat can alter protein synthesis by modulating the activity of the cytoskeleton, the proteasome and the expression of microRNAs translational repressers. We expect that results from this study will critically redefine our knowledge of Tat-mediated neurotoxicity, and can provide potential targets for more effective therapeutic intervention.