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

• 批准号: 8602712
• 负责人: Santosh Kumar
• 金额: $ 24.98万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8602712
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Adverse effects; Alcohols; Anti-Retroviral Agents; Biochemical; Biological Availability; Blood - brain barrier anatomy; Brain; Brain Injuries; CYP3A4 gene; Chronic; Cytochrome P-450 CYP2E1; Cytochrome P450; Development; Dose; Ethanol; Ethanol Metabolism; Goals; HIV; HIV-1; Highly Active Antiretroviral Therapy; Human; Immunosuppression; Impairment; In Vitro; Individual; Infiltration; Intervention; Knowledge; Lead; Liver; Lymphocyte; Mediating; Metabolism; Molecular; Oxidative Stress; Oxidative Stress Pathway; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Production; Protease Inhibitor; Quality of life; Reactive Oxygen Species; Regimen; Relative (related person); Reporting; Research; Ritonavir; Role; Testing; Toxic effect; Treatment Efficacy; Treatment outcome; Viral; Work; alcohol exposure; alcohol response; chronic alcohol ingestion; cytotoxicity; drug efficacy; improved; inhibitor/antagonist; macrophage; monocyte; neuroinflammation; neuropsychological; novel; novel therapeutic intervention; oxidative damage; problem drinker; public health relevance; response; treatment strategy

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)：众所周知，艾滋病毒感染者长期饮酒增加会增加艾滋病毒-1复制，并降低对高效抗逆转录病毒疗法(HAART)的反应。众所周知，酒精还可以破坏血脑屏障，进一步增加感染艾滋病毒的单核/巨噬细胞(主要病毒库)的中枢神经系统渗透，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(S)尚不清楚，特别是在单核/巨噬细胞中。据报道，通过各种刺激剂/途径产生的氧化应激是导致HIV-1复制增加的原因。乙醇诱导的细胞色素P450 2E1的表达是慢性酒精所致肝脏氧化应激的主要途径。由于已知CYP3A4可代谢重要的HAART药物--蛋白水解酶抑制物(PI)，因此其作用被认为是决定PIs生物利用度和疗效的关键。此外，乙醇和PI可诱导细胞色素P3A4的生成，可进一步增加PIs的代谢，从而降低其疗效。关于CYP通路在酒精介导的氧化损伤、HIV-1复制和单核/巨噬细胞PI代谢改变中的直接作用，人们知之甚少。我们的长期目标是明确CYP通路在酒精介导的氧化应激、HIV-1复制和单核/巨噬细胞对HAART反应中的作用，以及它们在神经艾滋病发病机制中的意义。我们的中心假设是，在单核/巨噬细胞中，酒精介导的氧化应激通过CYP2E1介导的途径导致HIV-1复制增强。此外，酒精介导的PI有效性的降低和PI介导的毒性的增加与HIV-1复制率的增加是通过CYP3A4直接介导的。为了检验我们的假设，我们提出了两个目标。目的1：研究乙醇对单核/巨噬细胞增殖抑制和HIV-1复制的影响，探讨细胞色素P42E1和3A4的作用。目的2：确定酒精感染HIV患者的单核/巨噬细胞特有的细胞、生化和分子变化。在成功完成这项拟议的研究后，我们预计已经确定CYP2E1参与了乙醇介导的氧化应激和HIV-1复制，并且酒精暴露改变了PI-CYP3A4相互作用，从而降低了酗酒HIV+患者的疗效PI。这些发现将为了解HIV-1的发病机制和HAART在酗酒/HIV+人群中的治疗策略开辟新的途径。