This Project will employ human monocyte-derived macrophages and primary microglia as indicator cells to test antiretroviral activities of several classes of anti-inflammatory and anti-oxidant compounds for treatments of HIV dementia.
The Specific Aims are: 1) Analyze the anti-retroviral activities of novel compounds for treatment of HIV dementia. Based on the hypothesis that secretory products from HIV-infected and uninfected immune activated macrophages/microglia produce neurotoxic activities, compounds to be tested will include glucocorticoids and their mediators (including lipocortin-1), quinolinic acid inhibitors, lexipafant (a PAF antagonist), BB-1101) (a metalloproteinase and TNF release inhibitor) and antiretroviral compounds (with avid blood-brain barrier penetration). Using a panel of HIV-1 isolates (including neurotropic isolates) the investigators will analyze the viral life cycle after drug treatment and virus infection. The drugs listed above will be inoculated into macrophage cultures (in a dose dependent manner) then infected with HIV-1 obtained from brain, blood and/or lymphoid tissues. 2) Test compounds in Specific Aim 1 for their ability to alter macrophage effector cell functions. A variety of inflammatory molecules (including proinflammatory cytokines, chemokines, eicosanoids, PAF, quinolinic acid, and excitatory amino acids (EAA)) thought most relevant for HIV dementia will be assayed following HIV-1 infection of monocytes (with/out immune activation) and microglia following drug treatment. These results will be correlated to changes in neurotoxic activities (including, in select experiments, neuronal electrophysiologic testing). 3) Developmental therapeutics. Promising compounds uncovered in projects I and II will be subjected to the identical testing outlined in Specific Aims 1 and 2. In addition, RP-HPLC, immunoaffinity chromatography, radioimmunoassays and cytokine bioassays will be used to identify potentially novel neurotoxic molecules produced from HIV-1-infected macrophages and/or microglia that may serve as therapeutic targets. Neuronal viability assays will determine the relationships (if any) between induced specific macrophage secretory activities (toxin production) and neuronal survival. 4) Use a SCID animal model for HIV encephalitis to test therapeutics for HIV. Histopathological alterations in brain tissue of SCID mice after inoculation of HIV-1-infected monocytes or microglia into the brain will serve s therapeutic endpoints to assess interventions. Correlations will be made between histopathology and levels of neurotoxins in infected CNS tissue. The antioxidant, anti-inflammatory and/or anti-retroviral compounds (tested initially within Specific Aims 1 and 2) will be given to the mice prior to challenge with virus-infected cells. Histopathologic changes with/out drug treatments with virus-infected cells. Histopathologic changes with/out drug treatments will asses drug efficacy.
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