AIDS, Immune Activation and Mental Health

艾滋病、免疫激活和心理健康

• 批准号: 7649264
• 负责人: Robert Dantzer
• 金额: $ 35.28万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649264
• 关键词: AIDS Dementia Complex; Accounting; Acids; Acquired Immunodeficiency Syndrome; Acute; Age; Anhedonia; Antiviral Therapy; Anxiety; Appearance; Astrocytes; Attenuated; Behavior; Behavioral; Biological; Brain; Cancer Patient; Cells; Cerebrospinal Fluid; Chronic; Clinical; Cognitive; Comorbidity; Consequences of HIV; Data; Depressed mood; Depressive disorder; Desire for food; Development; Dioxygenases; Disease; Dose; Encephalitis; Endogenous depression; Enzymes; Essential Amino Acids; Experimental Models; Fatigue; Feeling suicidal; General Population; Generations; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Hepatitis C; Highly Active Antiretroviral Therapy; Immune; Immune system; Immunotherapy; Infection; Inflammation Mediators; Interferon-alpha; Interleukin-2; Kynurenine; Laboratories; Major Depressive Disorder; Malignant Neoplasms; Mediating; Mental Health; Mental disorders; Metastatic Melanoma; Microglia; Minor; Molecular; Mood Disorders; Mus; Myeloid Cells; Neuroglia; Neurons; Neurotransmitters; Pathogenesis; Patients; Pattern; Peripheral; Personal Satisfaction; Phenotype; Plasma; Prevalence; Production; Proteins; Psychopathology; Quality of life; Reactive Oxygen Species; Renal carcinoma; Reporting; Research; Research Personnel; Rewards; Serotonin; Signal Transduction; Sleep; Structure; Symptoms; System; T-Lymphocyte; Testing; Trans-Activators; Tryptophan; Viral; Viral Proteins; base; cytokine; depression; depressive symptoms; falls; hypomania; in vivo; indoleamine; innovation; macrophage; motor disorder; neurochemistry; neuroinflammation; neuropathology; neurotoxic; neurotransmission; novel strategies; overexpression; prevent; programs; research study; response

DESCRIPTION (provided by applicant): Despite the progress of antiviral therapy, a majority of HIV-infected patients ultimately suffer from a variety of comorbid psychiatric illnesses, particularly major depressive disorders. These disorders impact patients' well-being and decrease their compliance with therapy, which can further compromise their quality of life. The mechanisms underlying the high comorbidity between HIV-1 infection and psychiatric disorders are still elusive. We have already established that proinflammatory cytokines produced by activated macrophages and T lymphocytes act in the brain to induce neurochemical and behavioral signs of depression in mice. In this condition, depressive-like behavior is associated with increased expression of indoleamine 2,3 dioxygenase (IDO), a key enzyme that regulates degradation of the essential amino acid tryptophan, and blockade of this enzyme abrogates depressive-like behavior. We propose that a similar mechanism accounts for HIV-associated depression. HIV-1 does not act directly on neurons but acts indirectly via glial cells through the generation of neurotoxic intermediates, such as proinflammatory cytokines and reactive oxygen species. When exposed to both viral glycoproteins (e.g., gp120) and/or transactivator viral proteins (e.g., Tat), virally infected macrophages and microglial cells synthesize these neurotoxic metabolites. In partial support of this hypothesis, we have obtained preliminary results indicating that repeated intracerebral administration of the viral glycoprotein gp120 to naive mice induces both depressive-like behavior and enhanced expression of brain IDO at doses that do not cause any sign of acute sickness. Based on these findings, we propose that the neuroinflammation induced by HIV proteins culminates in alterations of serotoninergic and dopaminergic neurotransmission that are at the origin of HIV-associated major depressive disorders. This hypothesis will be tested in three complementary objectives: (1) Do HIV proteins injected into the brain cause behavioral phenotypes of depression? Are these phenotypes also observed in mice with an inducible overexpression of Tat in astrocytes? (2) What is the neurochemical basis of the depressive-like behavioral effects of HIV proteins? And (3) Does targeting of brain inflammation at the level of microglial or IDO activation attenuate the functional consequences of HIV proteins on behavior and neurochemistry? Although the prevalence of clinical depression is much higher in HIV-infected patients than in the general population, the biological mechanisms that are responsible for this decline in mental health remain unknown. The research carried out in this project is needed to define potentially important cellular and molecular mechanisms that are used by HIV that results in depression, to identify the vulnerable brain structures that are responsible for this comorbid condition and to determine whether new pharmacological agents that negatively impact the ability of HIV to replicate can also alleviate the symptoms of depression in HIV-infected patients.

描述（由申请人提供）：尽管抗病毒疗法进展，但大多数受HIV感染的患者最终患有多种合并症的精神病，尤其是重度抑郁症。这些疾病会影响患者的福祉，并降低他们对治疗的依从性，这可能会进一步损害他们的生活质量。 HIV-1感染和精神疾病之间高度合并症的基础机制仍然难以捉摸。我们已经确定，活化的巨噬细胞和T淋巴细胞在大脑中产生的促炎细胞因子起作用，以诱导小鼠抑郁症的神经化学和行为迹象。在这种情况下，抑郁样行为与吲哚胺2,3二氧酶（IDO）的表达增加有关，这是一种调节必需氨基酸色氨酸降解的关键酶，该酶阻断了这种抑制作用抑郁症。我们提出，类似的机制是与HIV相关的抑郁症。 HIV-1不直接作用于神经元，而是通过神经毒性中间体（例如促炎性细胞因子和活性氧）通过神经胶质细胞间接起作用。当暴露于病毒糖蛋白（例如GP120）和/或反式激活因病毒蛋白（例如TAT）时，病毒感染的巨噬细胞和小胶质细胞合成这些神经毒性代谢物。为了部分支持这一假设，我们获得了初步结果，表明对天真小鼠的病毒性糖蛋白GP120重复施用会引起抑郁样的行为，并在没有引起任何急性疾病迹象的剂量下以抑郁样的行为和增强的脑IDO表达。基于这些发现，我们提出，HIV蛋白诱导的神经炎症最终导致血清素能和多巴胺能神经传递的改变，这是HIV相关的主要抑郁症的起源。该假设将以三个互补目标进行检验：（1）注入大脑的HIV蛋白是否会导致抑郁症的行为表型？在星形胶质细胞中TAT的诱导性过表达的小鼠中，这些表型是否也观察到？ （2）HIV蛋白的抑郁样行为作用的神经化学基础是什么？ （3）针对小胶质细胞或IDO激活水平的脑炎症的靶向减弱了HIV蛋白对行为和神经化学的功能后果？尽管艾滋病毒感染患者的临床抑郁症患病率比普通人群高得多，但导致这种心理健康下降的生物学机制仍然未知。需要在该项目中进行的研究来定义艾滋病毒所使用的潜在重要的细胞和分子机制，这些机制可导致抑郁症，以确定负责这种合并症的脆弱大脑结构，并确定对艾滋病毒复制能力复制能力的新药理药物是否还会减轻HIV受理患者抑郁症的症状。