HIV-Associated Dementia and the Urokinase Plasminogen Activation System

描述(申请人提供)：本申请的目的是研究尿激酶型纤溶酶原激活(UPA)系统在中枢神经系统(CNS)艾滋病毒感染及其最重要的临床后果-艾滋病毒痴呆(HIV-D)中的作用，以确定新的致病机制，并为临床管理(预防、诊断、预后和治疗)提供有用的标记。UPA系统由uPA及其受体uPAR、纤溶酶原激活物抑制物(PAI-1)和蛋白水解酶Nexin-1(PN-1)、第二纤溶酶原激活物tPA(组织型纤溶酶原激活剂)和各种结合分子组成，包括底物纤溶酶原和uPAR相互作用的甲酰肽受体样1(FPRL1)、整合素和玻璃连蛋白。这项拟议的研究将解决工作假说，即uPA系统可能通过与HIV在细胞水平上的相互作用以及随后uPA系统功能的失调，即细胞外蛋白分解和趋化作用，参与HIV-D的病理生理学。为此，实验方法将包括：1)测量脑脊液(CSF)和血浆中属于uPA系统或与uPA系统功能相关的关键分子的水平，以建立与HIV-D和其他艾滋病毒相关疾病、脑脊液中HIV-1复制和经典免疫激活CSF标记物的浓度以及HAART诱导的变化之间的联系；2)对未经ART治疗和HAART治疗的HIV相关损害或其他HIV相关疾病患者死后脑组织中相同分子的表达进行免疫组织化学研究。将评估细胞来源以及与其他标记物或艾滋病毒抗原的共同定位。3)单核/巨噬细胞培养系统中uPA系统与HIV-1相互作用的体外研究。尽管预期的结果只是相互关联的，但这些可能代表了其他模型的功能研究和新治疗策略评估的基础。

DESCRIPTION (provided by applicant): This application has the purpose of investigating the role of the urokinase plasminogen activation (uPA) system in HIV infection of the central nervous system (CNS) and its most important clinical consequence, HIV dementia (HIV-D), in order to define novel pathogenetic mechanisms and provide markers useful for clinical management (prevention, diagnosis, prognosis and treatment). The uPA system is composed of uPA, its receptor uPAR, its inhibitors plasminogen activator inhibitor (PAI-1) and protease nexin-1 (PN-1), a second plasminogen activator - tPA (tissue type plasminogen activator) and various binding molecules including the substrate plasminogen and the uPAR interactors formyl peptide receptor-like 1 (FPRL1), integrins and vitronectin. The proposed study will address the working hypothesis that the uPA system may be involved in the pathophysiology of HIV-D through interaction with HIV at a cellular level and subsequent dysregulation of uPA system functions, namely extracellular proteolysis and chemotaxis. To these aims, the experimental approach will include: 1) Measurement of cerebrospinal fluid (CSF) and plasma levels of key- molecules belonging to or functionally associated with the uPA system, in order to establish associations with HIV-D and other HIV-related conditions, HIV-1 replication in the CSF and concentrations of classical immune activation CSF markers, as well as the changes induced by HAART; 2) Immunohistochemical studies of expression of the same molecules in post-mortem brain tissues from both ART-untreated and HAART-treated patients with HIV-related lesions or other HIV-related conditions. Cellular source as well as co-localization with other markers or HIV antigens will be evaluated. 3) In vitro studies evaluating the mutual interactions between the uPA system and HIV-1 in monocytic/macrophage culture systems. Although expected findings will be only correlative, these might represent the basis for functional studies in other models and evaluation of new therapeutic strategies.