Microglia, Cytokines and HIV

小胶质细胞是HIV-1在中枢神经系统中的主要靶点，神经系统疾病（HAD/HIVE）的发生是HIV-1与胶质细胞相互作用导致神经元凋亡的结果。先前资助期的研究表明，在HIVE的中枢神经系统和人胶质细胞原代培养中，激活的小胶质细胞表达IL-1，诱导星形胶质细胞TNFalpha和INOS，导致神经元凋亡。IFNbeta下调神经胶质细胞的炎症激活并诱导抗hiv -1 β趋化因子（RANTES， mip -1 β和mip -1 α），提示IFNbeta在HIVE治疗中的作用。除IFNbeta外，许多巨噬细胞对外源性β趋化因子的抑制作用在这些条件下减弱。此外，在HIV-1感染的小胶质细胞中，β趋化因子通过与病毒复制相关的机制被诱导，MAP激酶在ifn β和hiv诱导的β趋化因子表达中发挥不同的作用。细胞因子诱导的人原代神经元凋亡是通过caspase依赖机制发生的，IFNbeta在该系统中表现出抗凋亡的特性。基于这些发现，我们提出以下具体目标。特异性目的1：确定巨噬细胞激活剂在小胶质细胞HIV-1感染中的作用。特异性目的2：确定RANTES在人神经胶质细胞中的诱导机制。特异性目的3：确定ifn β /趋化因子在细胞因子或hiv介导的神经毒性中的作用，并检查半胱天蛋白酶在这些过程中的作用。

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.