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，这可能进一步损害他们的生活质量。HIV-1感染和精神疾病之间高合并症的机制仍然难以捉摸。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，IDO是调节必需氨基酸色氨酸降解的关键酶，阻断该酶可消除抑郁样行为。我们提出类似的机制可以解释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（如促炎细胞因子和活性氧）的产生间接作用于神经胶质细胞。当暴露于病毒糖蛋白（如gp120）和/或反激活病毒蛋白（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，我们已经获得了初步结果，表明在不引起任何急性疾病迹象的情况下，向幼稚小鼠反复脑内注射病毒糖蛋白gp120可诱导抑郁样行为和增强脑IDO的表达。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相关重度抑郁症的起源。这一假设将在三个互补的目标中得到验证：(1)注射到大脑中的HIV蛋白是否会导致抑郁症的行为表型？在星形胶质细胞中诱导Tat过表达的小鼠中是否也观察到这些表型？(2) HIV蛋白产生抑郁样行为效应的神经化学基础是什么？(3)在小胶质细胞或IDO激活水平上靶向脑炎症是否会减弱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远高于一般人群，但导致这种精神健康下降的生物学机制仍不清楚。需要在本项目中进行的研究来确定导致抑郁症的艾滋病毒所使用的潜在重要细胞和分子机制，确定导致这种共病的脆弱大脑结构，并确定对艾滋病毒复制能力产生负面影响的新药理学药物是否也可以减轻艾滋病毒感染患者的抑郁症症状。

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.