Dopamine alters CNS migration of uninfected and HIV infected leukocytes to SDF-1

描述（由申请人提供）：尽管高效抗逆转录病毒疗法（HAART）已被证明对人类免疫缺陷病毒1 （HIV）感染者有效，但神经心理异常仍然是感染的主要临床问题。此外，在感染艾滋病毒的人群中有相当数量的药物滥用者，与感染艾滋病毒的非药物使用者相比，其中许多人的神经认知功能障碍加速和更严重。药物滥用加剧艾滋病毒感染者神经元损伤的机制尚未完全确定。一些研究发现，与没有药物滥用史的感染者或未感染艾滋病毒的药物滥用者相比，药物滥用增加了在艾滋病毒感染期间进入大脑的T淋巴细胞和单核细胞的数量。单核细胞进入中枢神经系统（CNS）已被证明在HIV感染的神经发病机制中起重要作用。单核细胞，以及T淋巴细胞，流入中枢神经系统有助于神经元损伤和随后发展的神经认知缺陷的HIV感染者。因此，单核细胞和T淋巴细胞流入中枢神经系统的机制特征将有助于设计临床策略，以限制HIV感染药物滥用者发生的神经认知功能障碍。许多滥用药物，包括可卡因和甲基苯丙胺，会提高中枢神经系统的细胞外多巴胺水平。我们有一个新的发现，多巴胺与趋化因子CXCL12 （SDF-1）协同作用，诱导未感染的人T淋巴细胞和单核细胞跨人血脑屏障（BBB）的体外模型迁移。此外，多巴胺降低血脑屏障内皮细胞中紧密连接蛋白claudin5的表达，这可能是多巴胺降低血脑屏障的不渗透性并促进白细胞转运的机制。因此，我们的假设是，在HIV感染的药物滥用者中，CNS细胞外多巴胺水平升高会加剧单核细胞和T淋巴细胞的浸润，无论是未感染的还是HIV感染的，以响应CXCL12进入CNS。这种白细胞内流可能导致中枢神经系统炎症增强、血脑屏障破坏、HIV进入和实质细胞感染以及神经元损伤。为了解决这个假设，我们将；1)表征CXCL12诱导未感染和HIV感染的T淋巴细胞和单核细胞跨血脑卒中转移的多巴胺调节，并确定激活有助于增强白细胞对CXCL12趋化的多巴胺受体；2)确定多巴胺受体激活如何调节T淋巴细胞和单核细胞对CXCL12的趋化反应，以及这些过程如何被HIV感染改变。3)分析多巴胺对血脑屏障细胞的影响，可能影响CXCL12诱导的未感染和HIV感染的T淋巴细胞和单核细胞的迁移。与公共卫生相关艾滋病毒感染者的神经问题日益严重，特别是如果这些人同时也是药物滥用者。我们建议研究艾滋病毒感染的药物滥用者对大脑的损害是如何增加的。这些研究的结果将为开发治疗神经功能障碍的疗法提供有用的信息，神经功能障碍是感染艾滋病毒的药物滥用者的主要临床问题。

DESCRIPTION (provided by applicant): Although highly active antiretroviral therapy (HAART) has proven effective in treating individuals infected with human immunodeficiency virus 1 (HIV), neuropsychological abnormalities are still major clinical problems of infection. In addition, there are significant numbers of drug abusers in the HIV infected population and many of these individuals have accelerated and more severe neurocognitive dysfunctions when compared to non-drug users infected with HIV. The mechanisms by which drugs of abuse exacerbate neuronal damage in the HIV infected population have not been completely characterized. Some studies have found that drug abuse increases the number of T lymphocytes and monocytes that enter the brain during HIV infection when compared to infected individuals without a history of drug abuse or to non-HIV infected drug abusers. Monocyte entry into the central nervous system (CNS) has been shown to play an important role in the neuropathogenesis of HIV infection. Monocyte, as well as T lymphocyte, influx into the CNS contributes to neuronal damage and the subsequent development of neurocognitive deficits in HIV infected individuals. Thus, characterization of the mechanisms of monocyte and T lymphocyte influx into the CNS would be beneficial in the design of clinical strategies to limit the neurocognitive dysfunctions that occur in HIV infected drug abusers. Many drugs of abuse, including cocaine and methamphetamine, elevate extracellular dopamine levels in the CNS. We have the novel finding that dopamine synergizes with the chemokine CXCL12 (SDF-1) in inducing uninfected human T lymphocyte and monocyte transmigration across an in vitro model of the human blood brain barrier (BBB). In addition, dopamine decreases the expression of the tight junction protein claudin 5 in BBB endothelial cells, a mechanism by which dopamine may decrease the impermeability of the BBB and promote leukocyte transmigration. It is therefore our hypothesis that elevated CNS levels of extracellular dopamine in HIV infected drug abusers exacerbates the infiltration of monocytes and T lymphocytes, both uninfected and HIV infected, into the CNS in response to CXCL12. This leukocyte influx may contribute to enhanced CNS inflammation, BBB disruption, HIV entry and infection of parenchymal cells, and neuronal damage. To address this hypothesis we will; 1) characterize dopamine modulation of CXCL12 induced uninfected and HIV infected T lymphocyte and monocyte transmigration across the BBB and identify the dopamine receptor(s) whose activation contributes to enhanced leukocyte chemotaxis to CXCL12, 2) determine how dopamine receptor(s) activation modulates the chemotactic response of T lymphocytes and monocytes to CXCL12 and how these processes are altered by HIV infection, and 3) analyze the effects of dopamine on the cells of the BBB that may affect CXCL12 induced uninfected and HIV infected T lymphocyte and monocyte transmigration. PUBLIC HEALTH RELEVANCE Neurological problems in HIV infected individuals are increasing in severity, especially if these individuals are also drug abusers. We propose to study how damage to the brain is increased in HIV infected drug abusers. The results of these studies will provide information that would be useful in the development of therapies to treat the neurologic dysfunctions that are major clinical problems in HIV infected drug abusers.