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(申请人提供)：脑内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，特别是在脑脊液病毒载量高的患者中。随着抗逆转录病毒疗法现已在全球范围内得到应用，这可能会成为一种最重要的神经并发症，对使用抗逆转录病毒药物治疗大量人群的能力产生重大影响，因为这些人群的病毒载量不易测量。了解这种综合征的发病机制并开发新的治疗方法在我们与艾滋病的斗争中至关重要。病理研究表明，在CNS IRIS患者中，大脑中有大量的T细胞渗透。我们实验室的初步数据表明，颗粒酶B(Granzyme B，GB)是激活的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可通过激活电压门控性钾通道KV1.3与神经细胞膜上的G蛋白偶联受体(GPCP)相互作用而引起神经毒性，从而导致神经细胞凋亡。这些观察结果挑战了传统观点，即GB需要穿孔素进入细胞，然后启动凋亡级联反应。我们还首次证明了Kv1.3通道的阻断剂具有神经保护特性。这些观察表明，有可能开发新的药理学方法来干预这种级联反应。在这份提案中，我们将重点放在了Kv1.3渠道上。该通道的药物阻滞剂不仅能拮抗Gb介导的神经毒性，而且还能阻止活化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细胞介导的神经炎性疾病也很重要。因此，我们提出了三个相互关联的具体目标。具体目的1：确定HIV蛋白是否能激活T细胞导致GB的释放。特异性目标2：确定GB介导的神经毒性机制特异性目标3：确定Kv1.3阻滞剂的神经保护机制