Macrophages and dopamine: a role in NeuroAIDS

描述(申请人提供)：这项提议的目的是增加对导致人类免疫缺陷病毒(HIV)感染的吸毒者神经系统并发症恶化的机制的了解。使用多巴胺能药物，如可卡因和甲基苯丙胺，会增加艾滋病毒感染者中艾滋病毒引起的神经系统疾病的发生率和严重性。这些药物通过增加中枢神经系统(CMS)的细胞外多巴胺水平来发挥作用。研究表明，细胞外多巴胺的增加加剧了HIV诱导的CMS病理，但介导这一作用的机制尚未完全确定。巨噬细胞是HIV在CMS中的主要靶点，在HIV感染的神经病理中也发挥着核心作用。这项提案中的初步数据显示，多巴胺治疗增加了巨噬细胞中艾滋病毒的复制，并证明了鳗鱼表面存在多巴胺受体。这些数据表明，多巴胺可能通过调节HIV感染巨噬细胞，在HIV诱导的CMS病理过程中发挥直接作用。为了确定介导这一效应的机制，本提案中的研究将充分表征多巴胺介导的巨噬细胞中艾滋病毒复制增加的药理学和动力学。在存在多巴胺受体激动剂和拮抗剂的情况下，HIV感染将决定哪些多巴胺受体介导巨噬细胞中HIV复制的增加。为了研究介导这一效应的机制，研究将检测活跃的多巴胺受体与HIV受体CD4、辅助受体CXCR4和CCR5之间的串扰，以及多巴胺在病毒进入、整合和萌发过程中诱导的变化。实验还将在HIV感染期间使用蛋白激酶抑制剂来检查与多巴胺增强HIV复制有关的信号通路。确定多巴胺增加巨噬细胞中艾滋病毒复制的机制将有助于理解和治疗艾滋病毒感染的吸毒者中神经系统疾病的高发病率和严重性。 公共卫生相关性：艾滋病毒感染可导致各种神经系统并发症，滥用药物会加剧这些并发症。明确药物滥用增加艾滋病毒引起的神经并发症的发生率和严重程度的机制将增加对艾滋病毒在大脑中感染的了解，并有助于制定干预策略，以限制艾滋病毒感染的吸毒者神经损害的破坏性后果。

DESCRIPTION (provided by applicant): The goal of this proposal is to increase the understanding of the mechanisms contributing the exacerbation of neurological complications in Human Immunodeficiency Virus (HIV) infected drug abusers. The use of dopaminergic drugs, such as cocaine and methamphetamine, increases both the incidence and severity of HIV-induced neurological disease in HIV infected individuals. These drugs act by increasing extracellular dopamine levels in the central nervous system (CMS). Studies show that increased extracellular dopamine exacerbates HIV induced CMS pathology, but the mechanisms that mediate this effect are not fully characterized. Macrophages, the major target for HIV in the CMS, also play a central role in the neuropathology of HIV infection. The preliminary data in this proposal show that dopamine treatment increases HIV replication in macrophages, and demonstrate the presence of dopamine receptors on the surface of the eels. These data indicate that dopamine may play a direct role in the development of HIV induced CMS pathology through dopamine mediated modulation of HIV infection of macropahges. To determine the mechanism mediating this effect, studies in this proposal will fully characterize the pharmacology and kinetics of dopamine-mediated increase in HIV replication in macrophages. HIV infection in the presence of dopamine receptor agonists and antagonists will determine which dopamine receptors mediate the increase in HIV replication in macrophages. To examine the mechanism mediating this effect, studies will examine crosstalk between the active dopamine receptors and the HIV receptor CD4, and coreceptors CXCR4 and CCR5 as well as dopamine-induced alterations in the viral entry, integration, and budding processes. Experiments will also use protein kinase inhibitors during HIV infection to examine the signaling pathways involved in dopamine enhanced HIV replication. Defining the mechanisms by which dopamine increases HIV replication in macrophages will contribute to the understanding and treatment of the heightened incidence and severity of neurological disease among HIV infected drug users. PUBLIC HEALTH RELEVANCE: HIV infection can result in a variety of neurological complications that are exacerbated by drugs of abuse. Defining the mechanisms by which drug abuse increases the incidence and severity of HIV induced neurological complications will increase the understanding of HIV infection in the brain and help to develop intervention strategies to limit the devastating consequences of neurologic impairment in HIV infected drug users.