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: 8242055
• 负责人: Peter Jesse Gaskill
• 金额: $ 14.61万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242055
• 关键词: AIDS neuropathy; Acceleration; Brain; Cells; Chemotaxis; Cocaine; Data; Development; Dopamine; Dopamine Receptor; Drug abuse; Eastern Europe; Far East; HIV; HIV Infections; Health; Human; Immune; Incidence; Individual; Infection; Inflammation; Inflammatory; Life; Macaca mulatta; Macrophage Activation; Mediating; Methamphetamine; Neuraxis; Neurologic; Neurotransmitters; Pathology; Pharmaceutical Preparations; Population; Production; Proteins; Research; SIV; Severities; Signal Pathway; Site; Source; System; Virus; abstracting; chemokine; cytokine; dopamine transporter; drug abuser; drug of abuse; extracellular; immune function; macrophage; methamphetamine abuse; nervous system disorder; neuroinflammation; neuropathology; pandemic disease; receptor-mediated signaling; response; success

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.

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