Neuropathogenesis of Immune Reconstitution Syndrome with HIV Infection

描述（由申请人提供）：脑免疫重建炎症综合征（IRIS）是一种破坏性疾病，在开始联合抗逆转录病毒治疗时可引起严重脑炎和死亡，特别是在脑脊液病毒载量高的患者中。随着抗逆转录病毒疗法在世界范围内的普及，这可能成为一种最重要的神经系统并发症，对无法轻易测量病毒载量的抗逆转录病毒药物治疗大量人群的能力产生重大影响。了解这种综合征的发病机制和开发新的治疗方法对我们与艾滋病的斗争至关重要。病理研究表明，在中枢神经系统IRIS患者中，大脑内有大量T细胞浸润。我们实验室的初步数据表明，颗粒酶B （GB）是激活T细胞释放的导致神经毒性的关键分子。此外，我们还观察到，GB可以通过与神经元细胞膜上的g蛋白偶联受体（GPCP）相互作用，激活电压门控钾通道Kv1，从而引起神经毒性。3导致神经元凋亡。这些观察结果挑战了传统观点，即GB需要穿孔素进入细胞，然后启动凋亡级联。我们也首次证明了Kv1.3通道的阻滞剂具有神经保护特性。这些观察结果表明，有可能开发出新的药理学方法来干预这种级联反应。在这个提案中，我们把精力集中在Kv1.3通道上。该通道的药物阻滞剂不仅可以防止GB介导的神经毒性，还可以防止活化T细胞释放GB，从而提供了一种新的治疗方法。这些观察结果可能对其他T细胞介导的神经炎症疾病也很重要。因此，我们提出三个相互关联的具体目标。特异性目的1：确定HIV蛋白是否能激活T细胞引起GB的释放。特异性目的2：确定GB介导的神经毒性机制。特异性目的3：确定Kv1.3阻滞剂的神经保护机制

DESCRIPTION (provided by applicant): Immune reconstitution inflammatory syndrome (IRIS) in the brain is a devastating disease that can cause severe encephalitis and death upon initiation of combination antiretroviral therapy particularly in patients with high CSF viral load. As antiretroviral therapy is now becoming available world wide this could emerge as a single most important neurological complication that will have a major impact on the ability to treat large populations with antiretroviral drugs where viral loads cannot be measured easily. Understanding the pathogenesis of this syndrome and developing new approaches for treatment are critically important in our battle against AIDS. Pathological studies suggest that in patients with CNS IRIS there is massive infiltration of T cells within the brain. Preliminary data from our laboratory suggest that granzyme B (GB) is the key molecule released by activated T cells that causes neurotoxicity. Furthermore, we have made a novel observation that GB can cause neurotoxicity by interaction with G-protein coupled receptors (GPCP) on the neuronal cell membrane with activation of a voltage gated potassium channel Kv1 .3 resulting in neuronal apoptosis. These observations challenge conventional wisdom that GB requires perforin to enter cells and then initiates the apoptotic cascade. We also demonstrate for the first time that blockers of the Kv1.3 channels have neuroprotective properties. These observations suggest that it may be possible to develop novel pharmacological approaches that could intervene in this cascade. In this proposal, we focused our efforts on the Kv1.3 channel. Pharmacological blockers of this channel not only protect against GB mediated neurotoxicity but also prevent GB release from activated T cells thus providing a novel therapeutic approach. These observations may also be important for other T cell mediated neuroinflammatory diseases. We thus propose three interrelated specific aims. Specific aim 1: To determine if HIV proteins can activate T cells to cause release of GB. Specific aim 2: To determine the mechanism of GB mediated neurotoxicity Specific aim 3: To determine the mechanism of neuroprotection with Kv1.3 blockers