Macrophages and dopamine: a role in NeuroAIDS

描述（由申请人提供）：本提案的目的是增加对人类免疫缺陷病毒（HIV）感染药物滥用者神经系统并发症加重机制的理解。使用多巴胺能药物，如可卡因和甲基苯丙胺，增加了HIV感染者中HIV诱导的神经系统疾病的发病率和严重程度。这些药物通过增加中枢神经系统（CMS）中的细胞外多巴胺水平起作用。研究表明，细胞外多巴胺的增加加剧了HIV诱导的CMS病理，但介导这种作用的机制并没有完全表征。巨噬细胞是CMS中HIV的主要靶点，在HIV感染的神经病理学中也起着核心作用。该提案中的初步数据表明，多巴胺治疗增加了巨噬细胞中的HIV复制，并证明了鳗鱼表面存在多巴胺受体。这些数据表明，多巴胺可能通过多巴胺介导的调节巨噬细胞的HIV感染，在HIV诱导的CMS病理学的发展中发挥直接作用。为了确定介导这种效应的机制，本提案中的研究将充分表征多巴胺介导的巨噬细胞中HIV复制增加的药理学和动力学。在多巴胺受体激动剂和拮抗剂存在下的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。为了研究介导这种效应的机制，研究将检查活性多巴胺受体和HIV受体CD4，辅助受体CXCR4和CCR 5之间的串扰，以及多巴胺诱导的病毒进入，整合和出芽过程的改变。实验还将在HIV感染期间使用蛋白激酶抑制剂来检查多巴胺增强HIV复制所涉及的信号通路。确定多巴胺增加HIV在巨噬细胞中复制的机制将有助于理解和治疗HIV感染吸毒者神经系统疾病的发病率和严重程度增加。 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，这些并发症因滥用药物而加剧。确定药物滥用增加艾滋病毒引起的神经系统并发症的发生率和严重程度的机制，将增加对大脑中艾滋病毒感染的了解，并有助于制定干预战略，以限制感染艾滋病毒的吸毒者神经系统损害的破坏性后果。

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.