Mechanisms of dopamine mediated increase in HIV infection of macrophages

多巴胺介导的巨噬细胞HIV感染增加的机制

• 批准号: 9333313
• 负责人: Peter Jesse Gaskill
• 金额: $ 40.02万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333313
• 关键词: Acute; Address; Adherence; Adjuvant Therapy; Affect; Aging; Alzheimer' s Disease; Animal Model; Anti-Retroviral Agents; Benserazide; Brain; CCR5 gene; Calcium; Calcium Signaling; Cells; Central Nervous System Diseases; Central Nervous System Infections; Comorbidity; Data; Development; Dopamine; Dopamine Antagonists; Dopamine Receptor; Dopaminergic Agents; Drug abuse; Drug usage; Drug user; Future; HIV; HIV Infections; HIV-associated neurocognitive disorder; Human; Illicit Drugs; In Vitro; Individual; Infection; Inflammatory; Integration Host Factors; Kinetics; Levodopa; Macaca; Macrophage Activation; Mediating; Membrane Fusion; Membrane Microdomains; Mental Depression; Microglia; Modeling; Molecular Conformation; Nervous System Trauma; Neuraxis; Neuroimmune; Neurologic; Neuropathogenesis; Parkinson Disease; Pharmaceutical Preparations; Pharmacology; Population; Primates; Process; Public Health; Regimen; SIV; Selegiline; Signal Transduction; Surface; System; Therapeutic; Therapeutic Uses; Treatment Protocols; Viral; Viral Load result; Viral reservoir; Virus; Virus Replication; age related; cofactor; combinatorial; dopamine system; drug abuser; extracellular; in vivo; inhibitor/antagonist; macrophage; neuroAIDS; neuroinflammation; neuropathology; neurotoxic; novel; novel therapeutic intervention; pre-exposure prophylaxis; prevent; public health relevance; response; scaffold; viral rebound

 DESCRIPTION (provided by applicant): Approximately 35 million people are infected with HIV worldwide. HIV enters the central nervous system (CNS) soon after initial infection, infecting primarily macrophages. Infected cells produce new virus and act as viral reservoirs within the CNS, enabling HIV to escape the effects of combinatorial anti-retroviral therapy (cART). Infected macrophages also release neurotoxic factors that contribute to the development of neuroinflammation and HIV-associated neurocognitive disorders (HAND). HIV+ drug abusers are especially vulnerable to the accelerated development of HIV-associated neuropathogenesis, and more than 10% of HIV+ individuals around the world abuse drugs. The mechanisms by which illicit drugs contribute to HIV-associated CNS damage are unclear, but all addictive substances increase extracellular dopamine in the CNS. We showed dopamine increases HIV replication in human macrophages by increasing the entry of the virus into these cells. The dopamine concentration that increases HIV entry is present in the CNS as a result of most types of drug abuse, indicating that CNS macrophages in HIV infected drug abusers are exposed to elevated dopamine. Thus, drug abuse could increase HIV entry into macrophages as soon as the virus enters the brain, rapidly expanding the size of the CNS reservoir and accelerating the development of HAND. The CNS is seeded before the initiation of cART, and even during cART low-level viral replication can persist in the CNS. Additionally, HIV+ drug abusers have poor adherence to cART and drug use during a break from therapy could significantly enhance the impact of the viral rebound. Thus, understanding the impact of dopamine on HIV infection of macrophages is essential to treatment of HIV+ drug abusers, even in the era of cART. This proposal will address this issue using both in vitro systems and a primate model of acute CNS infection in the presence of elevated dopamine. Our in vitro studies will precisely characterize the mechanism(s) by which dopamine increases HIV entry, suggesting new targets to be exploited as the basis for novel entry inhibitors or therapeutic strategies. The primate model will demonstrate the impact of dopamine in acute CNS infection in vivo, and provide a scaffold in which to examine the use of dopamine receptor antagonists with pre-exposure prophylaxis (PrEP) regimens, or as adjuvant therapy to be administered with cART in HIV+ drug abusers or others using therapeutics which affect the dopaminergic system. This system will also characterize the impact of dopamine on CNS infection and the neuroimmune response, providing contraindication data for clinicians using dopaminergic drugs in HIV+ individuals.

 描述（由申请人提供）： 全世界大约有 3500 万人感染艾滋病毒。 HIV 在初次感染后不久就进入中枢神经系统 (CNS)，主要感染巨噬细胞。受感染的细胞产生新病毒并充当中枢神经系统内的病毒储存库，使艾滋病毒能够逃避组合抗逆转录病毒疗法（cART）的影响。受感染的巨噬细胞还会释放神经毒性因子，导致神经炎症和 HIV 相关神经认知障碍 (HAND) 的发生。 HIV+ 药物滥用者特别容易受到 HIV 相关神经病变加速发展的影响，全世界超过 10% 的 HIV+ 个体滥用药物。非法药物造成艾滋病毒相关中枢神经系统损害的机制尚不清楚，但所有成瘾物质都会增加中枢神经系统的细胞外多巴胺。我们发现多巴胺通过增加病毒进入人类巨噬细胞来增加艾滋病病毒在这些细胞中的复制。由于大多数类型的药物滥用，中枢神经系统中存在增加艾滋病毒进入的多巴胺浓度，这表明感染艾滋病毒的药物滥用者的中枢神经系统巨噬细胞暴露于升高的多巴胺。因此，一旦病毒进入大脑，药物滥用就会增加艾滋病毒进入巨噬细胞的机会，从而迅速扩大中枢神经系统储存库的大小，并加速手足口病的发展。 CNS 在 cART 开始之前就被播种，即使在 cART 期间，低水平的病毒复制也可以在 CNS 中持续存在。此外，HIV+药物滥用者对 cART 的依从性较差，在治疗中断期间使用药物可能会显着增强病毒反弹的影响。因此，即使在 cART 时代，了解多巴胺对巨噬细胞 HIV 感染的影响对于治疗 HIV + 药物滥用者至关重要。该提案将使用体外系统和在多巴胺升高的情况下急性中枢神经系统感染的灵长类动物模型来解决这个问题。我们的体外研究将精确描述多巴胺增加艾滋病毒进入的机制，建议利用新的靶点作为新型进入抑制剂或治疗策略的基础。该灵长类动物模型将证明多巴胺在体内急性中枢神经系统感染中的影响，并提供一个支架，用于检查多巴胺受体拮抗剂与暴露前预防（PrEP）方案的使用，或作为辅助治疗与 cART 一起用于 HIV + 药物滥用者或其他使用影响多巴胺能系统的治疗方法。该系统还将表征多巴胺对中枢神经系统感染和神经免疫反应的影响，为临床医生在艾滋病毒+个体中使用多巴胺能药物提供禁忌数据。