IDO Regulation in the SIV Model of HIV CNS Disease

HIV CNS 疾病 SIV 模型中的 IDO 调节

• 批准号: 8022839
• 负责人: M CHRISTINE ZINK
• 金额: $ 59.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022839
• 关键词: Acute; Adverse effects; Animals; Archives; Astrocytes; Attention; Behavior; Blood specimen; Brain; Brain Drains; CD8B1 gene; Cardiovascular Physiology; Catabolism; Cell physiology; Cells; Central Nervous System Diseases; Chronic; Cytolysis; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Down-Regulation; Encephalitis; Endocrine; Endothelial Cells; Enzymes; Feedback; HIV; HIV Infections; Health; Highly Active Antiretroviral Therapy; Homeostasis; Immune response; Impaired cognition; In Vitro; Individual; Infection; Inflammation; Inflammatory; Kynurenine; Lead; Learning; Leukocytes; Lymphocyte Function; Lymphoid Tissue; Lymphoplasmacytoid Cell; Macaca; Mediating; Memory; Metabolism; Microglia; Modeling; Motor; Muscle Contraction; N-Methylaspartate; Nerve Degeneration; Neurons; Neurotransmitters; Oxygenases; Pathway interactions; Patients; Peripheral; Prevalence; Production; Prospective Studies; Protein Biosynthesis; Quality of life; Quinolinic Acid; Reaction; Regulation; SIV; Serotonin; Serotonin Production; Severities; Sleep; Staging; T-Lymphocyte; Temperature; Therapeutic; Time; Time Factors; Tissue Sample; Toxic effect; Tryptophan; Tryptophan Metabolism Pathway; Up-Regulation; Viral Load result; Virus; Virus Replication; aspartate receptor; cell mediated immune response; cell type; cytokine; excitotoxicity; immune activation; improved; in vivo; indolamine; macrophage; mood regulation; nervous system disorder; neuroinflammation; peripheral blood; prospective; raphe nuclei

DESCRIPTION (provided by applicant):While highly active antiretroviral therapy (HAART) has dramatically improved the quality of life for HIV-infected individuals, there has been an increase in the prevalence of HIV-associated neurological diseases. In fact, there is ongoing inflammation in the brains of HAART patients. Chronic HIV infection leads to the expression of a key enzyme in tryptophan metabolism, IDO (Indolamine 2, 3, Di-Oxygenase), which is upregulated during SIV/HIV infection. This enzyme dampens cell-mediated immune responses by diverting tryptophan to kynurenine (Kyn) metabolism. Activation of the normally silent Kyn pathway results in draining of tryptophan reserves. Tryptophan is essential for the production of neuroprotective serotonin, activation of effector T cells, and general protein synthesis throughout the body. The Kyn metabolite quinolinic acid leads to neurodegeneration by promoting NMDA (N-methyl-D-aspartic acid) receptor-mediated excitotoxicity. Other kynurenine metabolites, combined with the depletion of tryptophan, inhibit effector T-cell function, thus permitting more HIV replication in both the CNS and periphery. The net effect is more virus replication, greater CNS inflammation and upregulation of IFN3, which in turn further upregulates IDO, setting up a positive feedback loop that eventually leads to neuronal damage manifested as motor and cognitive dysfunction. In this application we will investigate the hypothesis that IDO is a central mechanism for the development of HIV-associated neurological disease, determine the extent and timing of IDO expression in brain and the periphery of SIV-infected animals, quantitate inducers of IDO expression (IFN3 and virus), identify IDO expressing cells in the CNS and periphery and define the consequences of IDO expression by quantitating tryptophan, kynurenine, kynurenine metabolites, inflammatory and neurodegeneration markers and viral load. We next will dissect the specific effects of IDO activation and inhibition on individual cell types from the brain and periphery in vitro. Finally we will investigate the consequences of IDO expression and inhibition in SIV-infected animals on serotonin levels in the brain and on effector T cell function in a prospective study. PUBLIC HEALTH RELEVANCE: Chronic activation of the immune regulatory enzyme IDO (Indolamine 2, 3, Di-Oxygenase) in the brains of HIV-infected individuals results in suppression of immune responses and increases in the number of infected and inflammatory cells in the brain. IDO consumes tryptophan (Trp) when active. Trp is required for synthesis of serotonin, a neurotransmitter that is critical for numerous brain functions including sleep, memory and learning, temperature regulation, mood, behavior, as well as systemic cardiovascular function, muscle contraction, and endocrine regulation. We propose that IDO is responsible for HIV neurological disease and the depletion of serotonin. We will study this using a well-characterized SIV model of HIV infection.

描述（由申请人提供）：虽然高度活跃的抗逆转录病毒疗法（HAART）显着改善了感染HIV感染的人的生活质量，但与HIV相关的神经系统疾病的患病率有所提高。实际上，HAART患者的大脑持续炎症。慢性HIV感染导致色氨酸代谢，IDO（吲哚胺2、3，二氧酶）中键酶的表达，该酶在SIV/HIV感染过程中被上调。这种酶通过将色氨酸转移到kynurenine（Kyn）代谢中来抑制细胞介导的免疫反应。正常静音的Kyn途径的激活导致色氨酸储量排出。色氨酸对于产生神经保护性5-羟色胺，效应T细胞的激活以及整个体内的一般蛋白质合成至关重要。 Kyn代谢产物喹啉酸通过促进NMDA（N-甲基-D-天冬氨酸）受体介导的兴奋性兴奋性兴奋性而导致神经变性。其他Kynurenine代谢产物与色氨酸的耗竭相结合，抑制效应T细胞功能，从而允许CNS和外围的HIV复制更多。净效应是更多的病毒复制，更大的中枢神经系统发炎和IFN3的上调，进而进一步上调了IDO，建立了一个正反馈环，最终导致神经元损伤表现为运动和认知功能障碍。在此应用中，我们将调查以下假设：IDO是发展与HIV相关神经系统疾病发展的核心机制，确定IDO表达在大脑中的表达程度和时间和时机，以及SIV感染的动物的周围，定量IDO表达的诱导剂（IFN3和病毒）的诱导剂（IFN3和病毒），识别IDO表达在CNS和围绕IDO中的表达，并在IDO中识别IDO的表达，并根据IDO的范围来定位IDO，并根据IDO的范围来定位IDO，并根据IDO的范围来定位。 Kynurenine，Kynurenine代谢产物，炎症和神经变性标记以及病毒载量。接下来，我们将在体外剖析IDO激活和抑制对单个细胞类型的特定作用。最后，在一项前瞻性研究中，我们将研究IDO表达和抑制SIV感染动物对大脑中5-羟色胺水平的后果。公共卫生相关性：免疫调节酶IDO的长期激活（吲哚胺2、3，二氧酶）在HIV感染的个体的大脑中导致抑制免疫反应并增加了大脑中感染和炎症细胞的数量。 Ido活跃时会消耗色氨酸（TRP）。 TRP是5-羟色胺的合成，这是一种神经递质，对于众多大脑功能至关重要，包括睡眠，记忆和学习，温度调节，情绪，行为以及全身心血管功能，肌肉收缩和内分泌调节。我们建议IDO负责HIV神经系统疾病和5-羟色胺的耗竭。我们将使用特征良好的HIV感染的SIV模型来研究这一点。