Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System

描述（由申请人提供）：在东欧和东南亚等世界地区，艾滋病毒在吸毒人群中的传播正在推动艾滋病毒大流行。随着 CART 的成功，艾滋病毒感染者的寿命更长，神经系统并发症正在成为一个重大的健康问题，特别是在感染艾滋病毒的吸毒者中。滥用甲基苯丙胺和可卡因的 HIV 感染者的神经病理学发生率和严重程度以及 HIV 相关神经系统疾病 (HAND) 的发生率显着增加。导致 HAND 加速的机制仍不清楚；然而，可卡因和甲基苯丙胺都是通过增加中枢神经系统 (CNS) 内神经递质多巴胺 (DA) 的细胞外水平来发挥作用。我们的研究结果表明，多巴胺会增加原代人类巨噬细胞中的 HIV 复制，而原代巨噬细胞是中枢神经系统中 HIV 感染的主要目标。我们的研究表明，巨噬细胞 HIV 复制的增加至少部分是由于 D2 样多巴胺受体的激活而感染了更多的巨噬细胞。此外，对感染猿猴免疫缺陷病毒的恒河猴的研究表明，细胞外多巴胺的增加会增强大脑内艾滋病毒的复制，并加剧中枢神经系统的病理。总之，这些研究表明，多巴胺对巨噬细胞 HIV 感染的影响可能是药物滥用加剧 HAND 发展的常见机制。巨噬细胞是中枢神经系统中艾滋病毒的主要目标和来源，也是主要的免疫应答者以及细胞因子和趋化因子的主要来源。细胞因子和趋化因子会增加神经炎症，并介导未感染的巨噬细胞募集到炎症部位，从而使病毒传播到未感染的巨噬细胞群体。我们的数据表明，多巴胺不仅增加巨噬细胞中的艾滋病毒复制，而且还激活多巴胺受体介导的信号传导，调节趋化蛋白的激活并改变细胞因子的产生。这些数据表明，药物引起的多巴胺增加不仅会增加中枢神经系统中艾滋病毒感染的程度，而且还可能增强艾滋病毒向未感染巨噬细胞的传播，并改变巨噬细胞对感染的反应。为了表征多巴胺增加巨噬细胞中 HIV 感染并改变巨噬细胞免疫功能的机制，我们将定义多巴胺介导的巨噬细胞中 HIV 复制周期的变化，检查巨噬细胞趋化性和炎性细胞因子/趋化因子产生的变化，并表征巨噬细胞中介导这些功能的 DR 信号通路。我们假设多巴胺会增加巨噬细胞中的 HIV 感染，并通过激活多巴胺受体和转运蛋白来改变巨噬细胞的功能，从而加剧 HIV 感染的吸毒者中 HAND 的发展。 公共卫生相关性：随着艾滋病毒感染者寿命的延长，神经系统并发症正在成为一个重大的健康问题，特别是在感染艾滋病毒的吸毒者中。药物滥用会增加艾滋病毒相关神经系统疾病的发病率和严重程度，但其发生机制尚不清楚。我们证明，多巴胺是所有滥用药物所共有的一种神经递质，它会增加巨噬细胞中艾滋病毒的复制，而巨噬细胞是大脑中艾滋病毒的主要靶细胞。我们建议定义多巴胺增加 HIV 复制的机制，并表征多巴胺介导的巨噬细胞功能变化。

DESCRIPTION (provided by applicant): In regions of the world such as Eastern Europe and South-East Asia, the HIV pandemic is being driven by the spread of HIV within drug-abusing populations. As HIV infected individuals live longer with the success of CART, neurological complications are emerging as a significant health issue, particularly among HIV-infected drug abusers. HIV infected individuals who abuse methamphetamine and cocaine show a significant increase in the incidence and severity of neuropathology and in the development of HIV-associated neurological disorders (HAND). The mechanism(s) leading to the acceleration HAND remain unclear; however, both cocaine and methamphetamine act by increasing in extracellular levels of the neurotransmitter dopamine (DA) within the central nervous system (CNS). Our findings demonstrate that dopamine increases HIV replication in primary human macrophages, which are the primary target for HIV infection in the CNS. Our research showed that this increase in macrophage HIV replication is due, at least in part, to the infection of greater numbers of macrophages through the activation of a D2-like dopamine receptor. Additionally, studies in simian immunodeficiency virus infected rhesus macaques showed that increased extracellular dopamine enhances intracerebral HIV replication and exacerbates central nervous system pathology. Together, these studies indicate that the effects of dopamine on HIV infection of macrophages could be a common mechanism by which drug abuse exacerbates the development of HAND. Macrophages are the primary targets and sources of HIV in the CNS, as well as a major immune responder and a major source of cytokines and chemokines. Cytokines and chemokines increase neuroinflammation and mediate the recruitment of uninfected macrophages to sites of inflammation, enabling the virus to spread to uninfected macrophage populations. Our data show that dopamine not only increases HIV replication in macrophages, but it activates dopamine receptor mediated signaling, modulates activation of chemotatic proteins and alters cytokine production. These data suggest that drug-induced increases in dopamine would not only increase the extent of HIV infection in the CNS, but could also enhance the spread of HIV to uninfected macrophages and alter the macrophage response to infection. To characterize the mechanism(s) by which dopamine increases HIV infection in macrophages and alters macrophage immune function, we will define dopamine mediated changes in the HIV replication cycle in macrophages, examine alterations in macrophage chemotaxis and production of inflammatory cytokines/chemokines, and characterize the DR signaling pathways in macrophages mediating these functions. We hypothesize that dopamine increases HIV infection in macrophages and alters macrophage functions through activation of dopamine receptors and transporter, contributing to the exacerbated the development of HAND in HIV infected drug abusers. PUBLIC HEALTH RELEVANCE: As HIV infected individuals live longer, neurological complications are emerging as a significant health issue, especially among HIV-infected drug abusers. Drug abuse increases the incidence and severity of HIV associated neurological disease, but the mechanism(s) by which this occurs are unclear. We demonstrated that dopamine, a neurotransmitter common to the actions of all drugs of abuse, increases HIV replication in macrophages, the major target cell for HIV in the brain. We propose to define the mechanism by which dopamine increases HIV replication and to characterize dopamine mediated changes in macrophage function.