Role of cytochrome P450 in alcohol-mediated effects on antiretroviral and HIV-1
细胞色素 P450 在酒精介导的抗逆转录病毒和 HIV-1 作用中的作用
基本信息
- 批准号:8918393
- 负责人:
- 金额:$ 32.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-20 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAdverse effectsAlcoholsAnti-Retroviral AgentsBiochemicalBiological AvailabilityBlood - brain barrier anatomyBrainBrain InjuriesCYP3A4 geneChronicCytochrome P-450 CYP2E1Cytochrome P450DevelopmentDoseEthanolEthanol MetabolismGoalsHIVHIV-1HealthHighly Active Antiretroviral TherapyHumanImmunosuppressionImpairmentIn VitroIndividualInfiltrationInterventionKnowledgeLeadLiverLymphocyteMediatingMetabolismMolecularOxidative StressOxidative Stress PathwayPathogenesisPathway interactionsPatientsPharmaceutical PreparationsProductionProtease InhibitorQuality of lifeReactive Oxygen SpeciesRegimenRelative (related person)ReportingResearchRitonavirRoleTestingToxic effectTreatment EfficacyTreatment outcomeViralWorkalcohol exposurealcohol responsechronic alcohol ingestioncytotoxicitydrug efficacyimprovedinhibitor/antagonistmacrophagemonocyteneuroAIDSneuroinflammationneuropsychologicalnovelnovel therapeutic interventionoxidative damageproblem drinkerresponsetreatment strategy
项目摘要
DESCRIPTION (provided by applicant): An increase in chronic alcohol consumption in HIV-infected individuals is known to increase HIV-1 replication and decrease responses to highly active antiretroviral therapy (HAART). Alcohol is also known to disrupt blood-brain barrier, which further increases the CNS infiltration of HIV-infected monocytes/ macrophages (major viral reservoir), leading to development of neuroAIDS. However, the underlying mechanism(s) by which alcohol exposure results in increased HIV-1 replication and decreased response to HAART drugs, especially in monocytes/macrophages, is not known. Oxidative stress generated through various stimulants/pathways has been reported to be responsible for increased HIV-1 replication. The major chronic alcohol-mediated oxidative stress pathway in the liver is ethanol-induced expression of cytochrome P450 2E1 (CYP2E1). Since CYP3A4 is known to metabolize important HAART drugs, protease inhibitors (PIs), the role of CYP3A4 is considered critical in determining the bioavailability and efficacy of PIs. In addition, CYP3A4 is known to be induced by ethanol and PI, which could result in further increases in metabolism of PIs, thereby, decreasing their efficacy. There is relatively little known about the direct contribution of CYP pathways in alcohol-mediated oxidative damage, HIV-1 replication, and altered metabolism of PIs in monocytes/macrophages. Our long-term goal is to define the role of CYP pathways in alcohol-mediated oxidative stress, HIV-1 replication, and response to HAART in monocytes/macrophages, and their implications in pathogenesis of neuroAIDS. Our central hypothesis is that in monocytes/macrophages alcohol-mediated oxidative stress causes enhanced HIV-1 replication via pathways mediated through CYP2E1. In addition, alcohol-mediated decrease in the efficacy of PIs and increase in PIs-mediated toxicity concurrent with increase in the rates of HIV-1 replication is directly mediated through CYP3A4. To test our hypothesis, we propose two aims. Aim 1: Examine the contribution of CYP2E1 and CYP3A4 in ethanol-mediated efficacy of PI and HIV-1 replication in monocytes/ macrophages. Aim 2: Determine cellular, biochemical, and molecular changes unique to monocytes/ macrophages derived from alcoholic HIV-infected patients. Upon successful completion of the proposed research, we expect to have established that CYP2E1 is involved in ethanol-mediated oxidative stress and HIV-1 replication and that alcohol exposure alters PI-CYP3A4 interaction, thereby, decreasing the efficacy PI in alcoholic HIV+ individuals. These finding will open a new avenue in understanding HIV-1 pathogenesis and HAART treatment strategy among alcoholic/HIV+ individuals.
描述(由申请人提供):已知HIV感染者慢性饮酒量的增加会增加HIV-1复制并降低对高效抗逆转录病毒治疗(HAART)的反应。酒精也被认为会破坏血脑屏障,进一步增加HIV感染的单核细胞/巨噬细胞(主要病毒库)的CNS浸润,导致神经艾滋病的发展。然而,酒精暴露导致HIV-1复制增加和对HAART药物反应降低的潜在机制(尤其是在单核细胞/巨噬细胞中)尚不清楚。据报道,通过各种兴奋剂/途径产生的氧化应激是增加HIV-1复制的原因。肝脏中主要的慢性酒精介导的氧化应激途径是乙醇诱导的细胞色素P450 2 E1(CYP 2 E1)表达。由于已知CYP 3A 4代谢重要的HAART药物,蛋白酶抑制剂(PI),因此认为CYP 3A 4在确定PI的生物利用度和疗效方面的作用至关重要。此外,已知乙醇和PI可诱导CYP 3A 4,这可能导致PI代谢进一步增加,从而降低其疗效。目前对酒精介导的氧化损伤、HIV-1复制和单核细胞/巨噬细胞中PI代谢改变的直接作用知之甚少。我们的长期目标是确定在酒精介导的氧化应激,HIV-1复制,并在单核细胞/巨噬细胞HAART反应,及其在neuroAIDS的发病机制的影响,ESTA途径的作用。我们的中心假设是,在单核细胞/巨噬细胞中,酒精介导的氧化应激通过CYP 2 E1介导的途径引起HIV-1复制增强。此外,酒精介导的PI疗效降低和PI介导的毒性增加以及HIV-1复制率增加均直接通过CYP 3A 4介导。为了验证我们的假设,我们提出了两个目标。目的1:检查CYP 2 E1和CYP 3A 4在单核细胞/巨噬细胞中PI和HIV-1复制的乙醇介导的功效中的作用。目的2:确定来自酒精性HIV感染患者的单核细胞/巨噬细胞特有的细胞、生化和分子变化。在成功完成拟议的研究后,我们预计已经确定CYP 2 E1参与乙醇介导的氧化应激和HIV-1复制,并且酒精暴露会改变PI-CYP 3A 4相互作用,从而降低酒精性HIV+个体中PI的疗效。这些发现将为理解酒精/HIV+个体中HIV-1发病机制和HAART治疗策略开辟新的途径。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Santosh Kumar其他文献
Santosh Kumar的其他文献
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Extracellular vesicles-based drug delivery of antiretroviral regimen to target CNS HIV reservoirs
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