HIV-Associated Dementia and the Urokinase Plasminogen Activation System

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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.