Neuropathogenesis of Immune Reconstitution Syndrome with HIV Infection

HIV感染免疫重建综合征的神经发病机制

• 批准号: 7228782
• 负责人: AVINDRA NATH
• 金额: $ 35.81万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228782
• 关键词: HIV infections; clinical research; neuroprotectants; neurotoxicology; proteins; syndrome

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

描述（由申请人提供）：大脑中的免疫重建炎症综合征（IRIS）是一种毁灭性疾病，可能导致严重的脑炎和死亡，启动抗逆转录病毒疗法后，特别是在CSF病毒较高的患者中。由于抗逆转录病毒疗法现在已经在全球范围内获得，因此可能会成为一种最重要的神经系统并发症，这将对无法轻松测量病毒载荷的抗逆转录病毒药物治疗大型种群的能力产生重大影响。在我们与艾滋病的斗争中，了解该综合征的发病机理和开发新方法的治疗方法至关重要。病理研究表明，在CNS虹膜患者中，大脑内T细胞大量浸润。我们实验室的初步数据表明，颗粒酶B（GB）是由激活的T细胞释放的关键分子，导致神经毒性。此外，我们已经进行了一个新的观察结果，即GB可以通过与GOTOTEIN偶联受体（GPCP）相互作用在神经元细胞膜上引起神经毒性，并激活电压盖型钾通道KV1 .3导致神经元凋亡导致神经元细胞膜。这些观察结果挑战了GB需要穿孔进入细胞，然后启动凋亡级联的传统观念。我们还首次证明了KV1.3通道的阻滞剂具有神经保护特性。这些观察结果表明，有可能开发出可以干预该级联的新型药理方法。在此提案中，我们将精力集中在KV1.3频道上。该通道的药理阻滞剂不仅可以防止GB介导的神经毒性，而且还可以防止GB从活化的T细胞中释放出来，从而提供了一种新型的治疗方法。这些观察结果对于其他T细胞介导的神经炎症性疾病也可能很重要。因此，我们提出了三个相互关联的特定目标。特定目标1：确定HIV蛋白是否可以激活T细胞引起GB的释放。特定目的2：确定GB介导的神经毒性特定目的的机理3：确定用KV1.3阻滞剂的神经保护机理