The Role of Osteopontin in HIV-Associated Neurocognitive Disorder

描述（由申请人提供）： HIV相关神经认知障碍（HAND）是一种多因素疾病，炎症和免疫激活是HAART后的突出特征。有一个关键的需要，以确定关键的主机因素，并了解他们的分子作用机制，有助于手。宏观经济在HAND的发展中起着核心作用。我们的长期目标是确定免疫/CNS轴上调节HIV-巨噬细胞相互作用的关键细胞通路，这些通路对神经元功能产生负面影响，导致HAND的发展。骨桥蛋白（OPN）是一种多功能的类精氨酸、分泌性糖磷蛋白，其在脑、脑脊液（CSF）和血浆中的过表达与神经退行性疾病相关，包括在HIV的非人灵长类动物模型中。然而，OPN与HAND神经元变性的直接联系尚未建立。我们确定OPN是HIV感染的巨噬细胞中上调的基因。巨噬细胞中OPN的敲低显著降低HIV复制，这表明OPN在病毒生命周期中起积极作用的新发现。与另一项研究相似，我们发现与轻度痴呆和HIV阴性对照受试者的CSF相比，患有严重认知障碍的HIV感染者的CSF中OPN水平显著升高。与未受损受试者相比，患有认知障碍的HIV感染患者的脑组织提取物中OPN也显著增加。我们认为，OPN通过其增加单核细胞募集到CNS中并刺激特定细胞因子/趋化因子和炎症途径的能力，在HAND的发展中起着核心作用。重要的是，这些OPN介导的通路可以提供新的潜在治疗靶点。我们的中心假设是巨噬细胞OPN的过度表达是宿主对HIV感染的反应，其作为反馈回路刺激进一步的巨噬细胞活化，从而触发导致神经元损伤和功能障碍的过程。两个目标将测试和检查这一假设：1）确定OPN表达是否与HAND中的神经元变性相关; 2）确定OPN调节HIV-1复制的分子机制。

DESCRIPTION (provided by applicant): HIV-associated neurocognitive disorder (HAND) is a multifactorial disease with inflammation and immune activation as prominent features that remain post-HAART. There is a critical need to identify key host factors and understand their molecular mechanisms of action contributing to HAND. Macrophages play a central role in the development of HAND. Our long-term goals are to identify key cellular pathways at the immune/CNS axis that modulate HIV-macrophage interactions which negatively impact neuronal function leading to the development of HAND. Osteopontin (OPN) is a multifunctional cytokine-like, secreted glycophosphoprotein whose over-expression in brain, cerebral spinal fluid (CSF) and plasma, is associated with neurodegenerative diseases including in non-human primate models of HIV. However, no direct link of OPN to neuronal degeneration in HAND has yet been established. We identified OPN as an upregulated gene in HIV-infected macrophages. Knockdown of OPN in macrophages significantly decreases HIV replication suggesting the novel finding that OPN plays a positive role in the viral life cycle. Similar to another study, we found significantly elevated OPN levels n the CSF of HIV-infected persons with severe cognitive disorder compared to CSF from mildly demented and HIV negative control subjects. OPN was also significantly increased in brain tissue extracts from HIV-infected patients with cognitive disorder compared to unimpaired subjects. We believe that OPN, through its ability to increase monocyte recruitment into the CNS and to stimulate specific cytokine/chemokine and inflammatory pathways, plays a central role in the development of HAND. Importantly, these OPN-mediated pathways could provide new potential therapeutic targets. Our central hypothesis is that over-expression of OPN from macrophages is a host response to HIV infection that acts as a feedback loop stimulating further macrophage activation that triggers processes leading to neuronal injury and dysfunction. Two aims will test and examine this hypothesis: 1) To determine whether OPN expression is associated with neuronal degeneration in HAND and 2) To identify the molecular mechanisms by which OPN modulates HIV-1 replication.