Modulation of cystatins and cathepsins in the neuropathogenesis of HIV-1 infection Cognitive impairment (CI) occurs during advanced HIV-1 infection, despite antiretroviral therapy (HAART). The molecular and cellular mechanisms for neuronal impairment evolve from neurotoxic secretory products produced from mononuclear phagocytes (MP;perivascular macrophages and microglia). Although the intracellular mechanisms that affect toxic MP secretions are incompletely known, the effector cell responses do play a pivotal role in CI. The long-term goal of the proposed study is to provide a better understanding of the role of macrophage secretory factors in homeostatic control during progressive HIV infection of the brain and to uncover novel targets for potential therapies. Among many secretory factors, cystatins and cathepsins secreted by MP play broad yet important roles in neuroregulatory responses. In particular, our laboratory and ex vivo experiments have shown the presence of cathepsins, cystatins, and SOD in virus-infected MP culture fluids and cerebrospinal fluid (CSF) of HIV-seropositive women with CI by proteomic analyses. Nevertheless, their role in neurodegenerative processes is not completely understood. The proposed study will elucidate the role played by cystatins and cathepsins, and SOD, on HIV-infected macrophages and their interactions with neuronal cells, which is critical for controlling the pro-inflammatory microenvironment in the brain during the induction of CI. We hypothesize that dysregulation of cystatins in HIV-infected macrophages during oxidative stress promotes cathepsin-B induced neurotoxicity and therefore contributes to CI. We will test this hypothesis with the following specific aims: 1) To determine, by analysis of gene and protein expression, how the interplay between cystatin B and cathepsin B regulates HIV-1 infection in macrophages and affects neurotoxic phenotype;2) To define the roles of cystatin B/C, cathepsin B, SOD, and proteins affected by their deregulation, found in Aim 1, as predictors of progression to CI in the presence of HAART. The significance and long-term implication of this study is that it will fill the gaps in knowledge regarding the interactions between cystatins, cathepsins and SOD in macrophages and their role in neuropathogenesis. The studies with the Hispanic cohort will also clarify the role of cystatins, cathepsins, and SOD in HIV-cognitive impairment in the post-HAART era. The proposed studies will determine the role of macrophage cystatins, cathepsins, SOD, and the proteins affected by their deregulation in HIV replication and neurotoxicity. The Hispanic cohort of HIV-infected women characterized for cognitive function and under antiviral therapy is an excellent source for the study of these possible biomarkers in the HAART era. The CSF, plasma, monocyte, and macrophage samples derived from this cohort have been stored longitudinally and provide an important source for testing our hypothesis: that over expression of cystatins in HIV-infected macrophages will promote cathepsin B-induced neurotoxicity and therefore contribute to CI. This study may elucidate novel targets for diagnosis and therapy.
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