Microglia, Cytokines and HIV

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Microglia are main targets of HIV-1 in the CNS, and neurological disease (HAD/HIVE) occurs as a result of interaction between HIV-1 and glial cells leading to neuronal apoptosis. Studies from the previous funding period have demonstrated that in the CNS of HIVE and in primary cultures of human glia, activated microglia express IL-1 which induces astrocyte TNFalpha and INOS, resulting in neuronal apoptosis. IFNbeta downregulates inflammatory activation of glial cells and induces anti-HIV-1 beta-chemokines (RANTES, MIP-1beta and MIP-1alpha), suggesting a role for IFNbeta as a therapy for HIVE. In addition to IFNbeta, a number of macrophage to the inhibitory effect of exogenous beta-chemokines diminishes under these conditions. Furthermore, beta-chemokines are induces in HIV-1 infected microglia by mechanisms linked to viral replication and MAP kinases play differential roles in IFNbeta- and HIV-induced beta-chemokine expression. Cytokine-induces apoptosis of primary human neurons occurs via caspases-dependent mechanisms and IFNbeta exhibits an anti-apoptotic property in this system. Based on these findings, we propose the following specific aims. Specific Aim 1: To determine the role of macrophage activators in HIV-1 infection of microglia. Specific Aim 2: To determine the mechanism of RANTES induction in human glia. Specific Aim 3: To determine the role of IFNbeta/chemokines in cytokine- or HIV-mediated neurotoxicity and to examine the role of caspases in these processes.