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

描述(申请人提供)：尽管高效抗逆转录病毒疗法(HAART)已被证明对感染人类免疫缺陷病毒1型(HIV)的患者有效，但神经心理异常仍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吸毒者，与感染艾滋病毒的非吸毒者相比，这些人中的许多人的神经认知功能障碍更严重。滥用药物加剧艾滋病毒感染人群神经元损伤的机制尚未完全确定。一些研究发现，与没有吸毒史的感染者或未感染艾滋病毒的吸毒者相比，吸毒增加了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)在HIV感染的神经发病机制中起重要作用。在HIV感染者中，单核细胞和T淋巴细胞进入中枢神经系统有助于神经元损伤和随后的神经认知障碍的发展。因此，表征单核细胞和T淋巴细胞进入中枢神经系统的机制将有助于临床策略的设计，以限制HIV感染的吸毒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细胞外多巴胺的水平。我们有一个新的发现，多巴胺与趋化因子CXCL12(SDF-1)在诱导未感染的人类T淋巴细胞和单核细胞跨越人血脑屏障(BBB)的体外模型中具有协同作用。此外，多巴胺还可减少血脑屏障内皮细胞紧密连接蛋白claudin 5的表达，这可能是多巴胺降低血脑屏障通透性和促进白细胞迁移的机制之一。因此，我们的假设是，HIV感染的吸毒者中枢神经系统细胞外多巴胺水平的升高加剧了未感染和HIV感染的单核细胞和T淋巴细胞对CXCL12的中枢神经系统的渗透。这种白细胞的流入可能导致中枢神经系统炎症增强、血脑屏障破坏、HIV侵入和实质细胞感染，以及神经元损伤。为了解决这一假说，我们将：1)鉴定多巴胺对CXCL12诱导的未感染和艾滋病毒感染的T淋巴细胞和单核细胞跨血脑屏障的迁移的调节作用，并确定其激活有助于增强白细胞对CXCL12的趋化作用的多巴胺受体(S)，2)确定多巴胺受体(S)如何激活调节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艾滋病毒感染改变，以及3)分析多巴胺对CXCL12诱导的未感染和艾滋病毒感染的T淋巴细胞和单核细胞迁移的影响。公共卫生相关性艾滋病毒感染者的神经系统问题日益严重，特别是如果这些人也是吸毒者的话。我们建议研究艾滋病毒感染的吸毒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提供有用的信息，这些神经功能障碍是艾滋病毒感染的吸毒者的主要临床问题。

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.