Neuropathogenesis of Immune Reconstitution Syndrome with HIV Infection

描述（由申请方提供）：大脑中的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导致严重脑炎和死亡，特别是在CSF病毒载量高的患者中。随着抗逆转录病毒疗法现在在全世界范围内普及，这可能成为一种最重要的神经系统并发症，将对用抗逆转录病毒药物治疗病毒载量不易测量的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在我们与艾滋病的斗争中至关重要。病理学研究表明，在CNS IRIS患者中，脑内存在大量T细胞浸润。我们实验室的初步数据表明，颗粒酶B（GB）是活化T细胞释放的导致神经毒性的关键分子。此外，我们已经作出了一个新的观察，GB可以通过与G-蛋白偶联受体（GPCP）的神经元细胞膜上的电压门控钾通道Kv1.3的激活，导致神经细胞凋亡的相互作用引起神经毒性。这些观察结果挑战了传统观念，即GB需要穿孔素进入细胞，然后启动凋亡级联反应。我们还首次证明Kv1.3通道阻滞剂具有神经保护特性。这些观察结果表明，有可能开发新的药理学方法，可以干预这一级联反应。在本提案中，我们将重点放在Kv1.3通道上。该通道的药理学阻断剂不仅防止GB介导的神经毒性，而且还防止GB从活化的T细胞释放，从而提供了一种新的治疗方法。这些观察结果对于其他T细胞介导的神经炎性疾病也可能是重要的。因此，我们提出三个相互关联的具体目标。具体目标1：确定HIV蛋白质是否可以激活T细胞以引起GB的释放。具体目标2：确定GB介导的神经毒性的机制具体目的3：确定Kv1.3阻断剂的神经保护机制

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