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: 8432832
• 负责人: M CHRISTINE ZINK
• 金额: $ 50.49万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432832
• 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.

描述（由申请人提供）：虽然高效抗逆转录病毒疗法 (HAART) 显着改善了 HIV 感染者的生活质量，但 HIV 相关神经系统疾病的患病率却有所增加。事实上，HAART 患者的大脑中存在持续的炎症。慢性 HIV 感染会导致色氨酸代谢中关键酶 IDO（吲哚胺 2, 3，二加氧酶）的表达，该酶在 SIV/HIV 感染期间上调。这种酶通过将色氨酸代谢转变为犬尿氨酸 (Kyn) 来抑制细胞介导的免疫反应。通常沉默的 Kyn 通路的激活会导致色氨酸储备的耗尽。色氨酸对于神经保护性血清素的产生、效应 T 细胞的激活以及全身蛋白质的合成至关重要。 Kyn 代谢物喹啉酸通过促进 NMDA（N-甲基-D-天冬氨酸）受体介导的兴奋性毒性而导致神经变性。其他犬尿氨酸代谢物与色氨酸的消耗相结合，抑制效应 T 细胞功能，从而允许更多的 HIV 在 CNS 和外周复制。净效应是更多的病毒复制、更大的中枢神经系统炎症和 IFN3 的上调，这反过来又进一步上调 IDO，建立一个正反馈循环，最终导致表现为运动和认知功能障碍的神经元损伤。在此应用中，我们将研究 IDO 是 HIV 相关神经系统疾病发展的核心机制的假设，确定 SIV 感染动物大脑和外周中 IDO 表达的程度和时间，定量 IDO 表达诱导剂（IFN3）和病毒），鉴定中枢神经系统和外周中的 IDO 表达细胞，并通过定量色氨酸、犬尿氨酸、犬尿氨酸代谢物、炎症和神经退行性标记物来定义 IDO 表达的后果和病毒载量。接下来我们将在体外剖析 IDO 激活和抑制对大脑和外周个体细胞类型的具体影响。最后，我们将在一项前瞻性研究中研究 SIV 感染动物中 IDO 表达和抑制对大脑中血清素水平和效应 T 细胞功能的影响。

项目成果

Early minocycline treatment prevents a decrease in striatal dopamine in an SIV model of HIV-associated neurological disease.

• DOI: 10.1007/s11481-011-9332-1
• 发表时间: 2012-06
• 期刊: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
• 作者: Meulendyke KA;Pletnikov MV;Engle EL;Tarwater PM;Graham DR;Zink MC
• 通讯作者: Zink MC

Modulation of HIV-1-induced activation of plasmacytoid dendritic cells by 6-desfluoroquinolones.

6-去氟喹诺酮类药物调节 HIV-1 诱导的浆细胞样树突状细胞活化。

• DOI: 10.1089/aid.2013.0154
• 发表时间: 2014
• 期刊: AIDS research and human retroviruses
• 影响因子: 1.5
• 作者: Royle,CarolineM;Tsai,Ming-Han;Tabarrini,Oriana;Massari,Serena;Graham,DavidR;Aquino,VeronicaN;Boasso,Adriano
• 通讯作者: Boasso,Adriano

Two new tryptophan derivatives from the seed kernels of Entada rheedei: effects on cell viability and HIV infectivity.

来自 Entada rheedei 种仁的两种新色氨酸衍生物：对细胞活力和 HIV 感染性的影响。

• DOI: 10.1016/j.fitote.2013.03.017
• 发表时间: 2013
• 期刊: Fitoterapia
• 影响因子: 3.4
• 作者: Nzowa,LK;Teponno,RB;Tapondjou,LA;Verotta,L;Liao,Z;Graham,D;Zink,M-C;Barboni,L
• 通讯作者: Barboni,L

Integrated microfluidic chip and online SCX separation allows untargeted nanoscale metabolomic and peptidomic profiling.

集成微流控芯片和在线 SCX 分离可实现非靶向纳米级代谢组学和肽组学分析。

• DOI: 10.1021/pr5011422
• 发表时间: 2015
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: Tharakan,Ravi;Tao,Dingyin;Ubaida-Mohien,Ceereena;Dinglasan,RhoelR;Graham,DavidR
• 通讯作者: Graham,DavidR