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3500万人感染了艾滋病毒。初次感染后不久，HIV进入中枢神经系统（CNS），感染原发性巨噬细胞。感染的细胞产生新的病毒并充当中枢神经系统中的病毒储量，从而使HIV逃脱了组合抗逆转录病毒治疗（CART）的作用。感染的巨噬细胞还释放神经毒性因子，这些因素有助于神经炎症和与HIV相关的神经认知疾病（HAND）。艾滋病毒+药物滥用者尤其容易受到与艾滋病毒相关的神经病发生的加速发展，以及世界上超过10％的艾滋病毒+个体滥用药物。非法药物导致与HIV相关的中枢神经系统损伤的机制尚不清楚，但所有其他物质都会增加中枢神经系统的细胞外多巴胺。我们表明，多巴胺通过增加病毒进入这些细胞而增加了人类巨噬细胞中的HIV复制。大多数类型的药物滥用，在中枢神经系统中提出了增加HIV进入的多巴胺浓度，这表明HIV感染的药物滥用者中的CNS巨噬细胞暴露于多巴胺升高。这一点，药物滥用可能会在病毒进入大脑后立即增加艾滋病毒进入巨噬细胞，迅速扩大中枢神经系统水库的大小并加速手的发展。在开始推车之前，将中枢神经系统接种了，即使在CART期间，低级病毒复制也可以持续存在于中枢神经系统中。此外，艾滋病毒+药物滥用者对货车的依从性较差，在休息期间使用毒品可以显着增强病毒反弹的影响。这就是了解多巴胺对巨噬细胞的艾滋病毒感染的影响，即使在购物车时代，也至关重要。该提案将使用体外系统既可以解决此问题，并且我们的体外研究将准确地表征多巴胺增加HIV进入的机制，这表明将探索新的靶标作为新型进入抑制剂或治疗策略的基础。私人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，并提供一个脚手架，以检查具有暴露前预防（PREP）治疗方案的多巴胺受体的使用，或者作为调整疗法的使用，或作为调整疗法，以在HIV+药物虐待者或其他疗法中使用CART施用，以影响多发性药物系统。该系统还将表征多巴胺对CNS感染和神经免疫反应的影响，从而为使用HIV+个体中多巴胺能药物的临床医生提供禁忌症数据。