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，但大多数艾滋病毒感染者最终都患有各种精神疾病，特别是严重的抑郁症。这些疾病影响患者的幸福感，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的高共患率背后的机制仍然难以捉摸。我们已经证实，由激活的巨噬细胞和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双加氧酶(IDO)的表达增加有关，吲哚胺2，3双加氧酶(IDO)是调节必需氨基酸色氨酸降解的关键酶，阻断该酶可取消抑郁样行为。我们认为，艾滋病毒相关性抑郁症也有类似的机制。HIV-1不直接作用于神经元，而是通过产生神经毒性中间体，如促炎细胞因子和活性氧物种，间接作用于神经胶质细胞。当同时接触病毒糖蛋白(例如gp120)和/或反式激活病毒蛋白(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。作为对这一假说的部分支持，我们获得了初步结果，表明在不会导致任何急性疾病迹象的剂量下，对幼鼠重复脑内注射病毒糖蛋白gp120可以诱导抑郁样行为和增强脑IDO的表达。基于这些发现，我们认为HIV蛋白诱导的神经炎症最终导致5-羟色胺和多巴胺能神经传递的改变，而这两种神经传递是HIV相关的主要抑郁障碍的起源。这一假设将在三个相辅相成的目标中得到检验：(1)注射到大脑中的艾滋病毒蛋白是否会导致抑郁症的行为表型？这些表型在星形胶质细胞中诱导过表达TAT的小鼠中也观察到了吗？(2)HIV蛋白抑郁样行为效应的神经化学基础是什么？以及(3)以小胶质细胞或IDO激活水平的脑部炎症为靶点是否会减弱HIV蛋白对行为和神经化学的功能影响？尽管HIV感染患者的临床抑郁患病率比普通人群高得多，但导致精神健康下降的生物机制仍不清楚。在这个项目中开展的研究需要确定艾滋病毒用于导致抑郁的潜在重要的细胞和分子机制，确定导致这种共病的脆弱的大脑结构，并确定对艾滋病毒复制能力产生负面影响的新的药理制剂是否也可以缓解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.