AIDS, Immune Activation and Mental Health

描述（由申请人提供）：尽管抗病毒治疗取得了进展，但大多数HIV感染患者最终患有各种共病精神疾病，特别是重度抑郁症。这些疾病影响患者的健康，降低他们对治疗的依从性，这可能进一步影响他们的生活质量。HIV-1感染和精神疾病之间高度共病的机制仍然是难以捉摸的。我们已经确定，由活化的巨噬细胞和T淋巴细胞产生的促炎细胞因子在大脑中起作用，诱导小鼠抑郁症的神经化学和行为体征。在这种情况下，抑郁样行为与吲哚胺2，3双加氧酶（IDO）的表达增加有关，IDO是调节必需氨基酸色氨酸降解的关键酶，阻断这种酶可消除抑郁样行为。我们认为，一个类似的机制占艾滋病毒相关的抑郁症。HIV-1不直接作用于神经元，而是通过神经胶质细胞产生神经毒性中间体（如促炎细胞因子和活性氧）间接作用。当暴露于两种病毒糖蛋白（例如，gp 120）和/或反式激活病毒蛋白（例如，达特）、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。在部分支持这一假设，我们已经获得了初步的结果表明，反复脑内给药的病毒糖蛋白gp 120幼稚小鼠诱导抑郁样行为和脑IDO的表达增强的剂量，不引起任何急性疾病的迹象。基于这些发现，我们提出，由HIV蛋白诱导的神经炎症最终导致了多巴胺能和多巴胺能神经传递的改变，这些改变是HIV相关的重度抑郁症的起源。这一假设将在三个互补的目标进行测试：（1）注射到大脑中的HIV蛋白是否会导致抑郁症的行为表型？这些表型是否也在星形胶质细胞中诱导性过表达达特的小鼠中观察到？(2)HIV蛋白质的抑郁样行为效应的神经化学基础是什么？以及（3）在小胶质细胞或IDO激活水平上靶向脑炎症是否减弱了HIV蛋白对行为和神经化学的功能性后果？虽然临床抑郁症在艾滋病毒感染者中的患病率比一般人群高得多，但导致心理健康下降的生物机制仍然未知。在这个项目中进行的研究是必要的，以确定潜在的重要的细胞和分子机制，是由艾滋病毒使用，导致抑郁症，以确定脆弱的大脑结构，负责这种共病的条件，并确定是否新的药理学代理，负面影响艾滋病毒的能力复制也可以减轻艾滋病毒感染患者的抑郁症状。

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.