Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System

多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病

• 批准号: 8637953
• 负责人: Peter Jesse Gaskill
• 金额: $ 14.02万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637953
• 关键词: AIDS neuropathy; Acceleration; Acquired Immunodeficiency Syndrome; Award; Biology; Brain; CCR5 gene; Cells; Cellular biology; Chemotaxis; Cocaine; Data; Development; Dopamine; Dopamine Receptor; Drug Addiction; Drug abuse; Eastern Europe; Education; Faculty; Far East; Focal Adhesions; Grant; HIV; HIV Infections; Health; Human; Immune; Incidence; Individual; Infection; Inflammation; Inflammatory; Knowledge; Laboratories; Learning; Life; Macaca mulatta; Macrophage Activation; Mediating; Mentors; Methamphetamine; Methodology; Molecular; Molecular Biology; Neuraxis; Neurologic; Neuropharmacology; Neurotransmitters; New York; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Population; Production; Proteins; Research; Retroviridae; SIV; Scientist; Severities; Signal Pathway; Signal Transduction; Site; Societies; Source; System; Techniques; Universities; Virus; Work; Writing; abstracting; addiction; cell motility; chemokine; cytokine; design; dopamine transporter; drug abuser; drug of abuse; extracellular; immune function; kinase inhibitor; macrophage; meetings; methamphetamine abuse; nervous system disorder; neuroinflammation; neuropathology; pandemic disease; programs; receptor; receptor-mediated signaling; research study; response; skills; success; symposium; trafficking

Abstract: 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.

抽象的： 在东欧和东南亚等世界的地区，艾滋病毒大流行是由艾滋病毒在滥用毒品的人群中的传播所驱动的。随着艾滋病毒感染的人的寿命更长，随着购物车的成功，神经系统并发症正在成为一个重大的健康问题，尤其是在艾滋病毒感染的药物滥用者中。滥用甲基苯丙胺和可卡因的艾滋病毒感染者在神经病理学的发病率和严重程度以及与HIV相关的神经系统疾病的发展（HAND）的发生上显着增加。导致加速手的机制仍不清楚。然而，可卡因和甲基苯丙胺都通过增加中枢神经系统（CNS）内神经递质多巴胺（DA）的细胞外水平来起作用。我们的发现表明，多巴胺在原代人巨噬细胞中增加了HIV复制，这是CNS中HIV感染的主要靶标。我们的研究表明，巨噬细胞HIV复制的增加至少部分是由于通过激活D2样多巴胺受体感染了更多数量的巨噬细胞。此外，在感染恒河猴的猿猴免疫缺陷病毒中的研究表明，增加了 细胞外多巴胺增强了脑内HIV复制，并加剧了中枢神经系统病理。总之，这些研究表明，多巴胺对巨噬细胞的艾滋病毒感染的影响可能是药物滥用加剧手发的常见机制。巨噬细胞是中枢神经系统中HIV的主要靶标和来源，也是主要的免疫响应者，也是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，从而使病毒扩散到未感染的巨噬细胞群体。我们的数据表明，多巴胺不仅增加了巨噬细胞中的HIV复制 它激活多巴胺受体介导的信号传导，调节化学蛋白的激活并改变细胞因子的产生。这些数据表明，药物诱导的多巴胺增加不仅会增加中枢神经系统的HIV感染程度，而且还可以增强HIV对未感染的巨噬细胞的传播，并改变巨噬细胞对感染的巨噬细胞反应。为了表征多巴胺在巨噬细胞中增加HIV感染并改变巨噬细胞免疫功能的机制，我们将定义多巴胺在巨噬细胞中介导的HIV复制周期中介导的变化，检查巨噬细胞趋化性的变化以及炎症性细胞因子/趋化因子/趋化性趋化途径的炎症性促进和促成莫克型的促进型的变化。我们假设多巴胺会通过激活多巴胺受体和转运蛋白来增加巨噬细胞中的HIV感染，并改变巨噬细胞的功能，从而加剧了HIV感染的药物滥用者的手术。