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: 7294321
• 负责人: AVINDRA NATH
• 金额: $ 34.83万
• 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/7294321
• 关键词: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Apoptotic; Brain; Cell membrane; Cells; Cessation of life; Complication; Data; Disease; Encephalitis; G-Protein-Coupled Receptors; HIV; HIV Infections; Immune; Infiltration; Inflammatory; Laboratories; Measures; Mediating; Neurologic; Neurons; Neuropathogenesis; Pathogenesis; Patients; Pharmaceutical Preparations; Population; Property; Proteins; Syndrome; T-Lymphocyte; Time; Viral Load result; Voltage-Gated Potassium Channel; antiretroviral therapy; channel blockers; granzyme B; neuron apoptosis; neuroprotection; neurotoxicity; novel; novel strategies; novel therapeutics; perforin; prevent; reconstitution

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）是一种破坏性疾病，在开始联合抗逆转录病毒治疗后可导致严重脑炎和死亡，特别是对于脑脊液病毒载量高的患者。随着抗逆转录病毒疗法现已在全世界范围内普及，这可能会成为一种最重要的神经系统并发症，将对使用抗逆转录病毒药物治疗大量无法轻易测量病毒载量的人群的能力产生重大影响。了解这种综合征的发病机制并开发新的治疗方法对于我们抗击艾滋病至关重要。病理学研究表明，CNS IRIS 患者大脑内存在大量 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，我们还发现，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 .3 导致神经元凋亡，从而引起神经毒性。这些观察结果挑战了 GB 需要穿孔素进入细胞然后启动细胞凋亡级联的传统观点。我们还首次证明 Kv1.3 通道阻断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一级联反应。在这个提案中，我们将重点放在 Kv1.3 通道上。该通道的药理学阻断剂不仅可以防止 GB 介导的神经毒性，还可以防止活化的 T 细胞释放 GB，从而提供一种新的治疗方法。这些观察结果对于其他 T 细胞介导的神经炎症疾病也可能很重要。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 蛋白是否可以激活 T 细胞导致 GB 释放。具体目标 2：确定 GB 介导的神经毒性机制 具体目标 3：确定 Kv1.3 阻滞剂的神经保护机制