Tobacco/nicotine, cytochrome P450, and HIV-1

烟草/尼古丁、细胞色素 P450 和 HIV-1

• 批准号: 8138968
• 负责人: Santosh Kumar
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138968
• 关键词: AIDS neuropathy; Acetylcysteine; Acquired Immunodeficiency Syndrome; Africa; Alveolar Macrophages; Antioxidants; Attention; Blood; Brain; Butanones; Cameroon; Categories; Cell Line; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Cotinine; Coumarins; Cytochrome P450; DNA; Development; Dimensions; Foundations; Future; General Population; Genetic Polymorphism; Goals; HIV; HIV-1; Human; Immune response; Individual; Infection; Inflammation; Leukocytes; Link; Liver; Lung; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Mediating; Messenger RNA; Metabolic Pathway; Metabolism; Methionine; Methoxsalen; Microglia; Modeling; N' -nitrosonornicotine; National Institute of Drug Abuse; Neurons; Nicotine; Oxidative Stress; Population; Prevalence; Proteins; Reactive Oxygen Species; Recruitment Activity; Reporting; Research; Risk; Role; Smoker; Smoking; Substance of Abuse; Superoxide Dismutase; Techniques; Testing; Therapeutic Agents; Tobacco; Tobacco use; Tryptamines; U937 Cells; Virus; Woman; Work; alpha benzopyrone; antiretroviral therapy; catalase; cellular targeting; cigarette smoking; comparative; design; inhibitor/antagonist; macrophage; monocyte; non-smoker; novel; novel therapeutics; response; smoking prevalence

DESCRIPTION (provided by applicant): The potential impact of cigarette smoking in HIV scenario can be gauged from the fact that the prevalence of smoking is estimated to be 50-70% in HIV+ population compared to 20% in the general population. Until recently, little attention was paid to the potential interaction between smoking and HIV-1/AIDS. Smoking and its main constituent, nicotine have been shown to enhance HIV-1 replication in alveolar macrophages and microglia, decrease immune responses, and decreased responses to antiretroviral therapy (ART). However, very little is known about the mechanism(s) by which nicotine causes these effects. Nicotine, its major metabolite, cotinine, and other important tobacco-specific compounds are predominantly metabolized by cytochrome P450 2A6 (CYP2A6), especially in the liver, and by lung-specific CYP2A13. This metabolic pathway is thought to increase oxidative stress and inflammation, resulting in liver damage, as well as lung, esophageal, and pancreatic cancers. Several studies, including ours, demonstrate that CYP2A6 is highly expressed in human monocyte-derived macrophages. Our preliminary studies show that CYP2A6 is induced by nicotine in U937 cell lines (HIV-1 model cell lines for macrophages). However, their clinical implications are unknown. Macrophages are one of the major cellular targets of HIV-1, crucial virus reservoirs, and carriers of HIV-1 infection to the brain (NeuroAIDS). Our goal is to examine the role of nicotine in CYP2A6-induced oxidative stress and HIV-1 replication in macrophages. Our hypothesis is that nicotine enhances HIV-1 replication in macrophages through CYP2A6-mediated nicotine metabolism and oxidative stress. To test the hypothesis, the study is designed with two specific aims. Specific Aim 1: To examine the role of nicotine on CYP2A6-mediated oxidative stress and HIV-1 replication in human primary macrophages. Specific Aim 2: To determine the effect of smoking on CYP2A6 expression, oxidative stress, and HIV-1 replication in HIV+ smokers. Upon successful completion of this project, we will have tested our hypothesis that nicotine enhances HIV-1 replication through CYP2A6-mediated oxidative stress in human macrophages. This would provide the first evidence of the effect of nicotine on HIV-1 replication in macrophages and the mechanism by which it occurs. This novel work would provide a new dimension in HIV-1/nicotine related research, and would provide an opportunity to develop novel therapeutic agents to treat HIV+ smokers effectively. PUBLIC HEALTH RELEVANCE: The proposal will examine the role of smoking/nicotine on CYP2A6-mediated oxidative stress in HIV-1 replication. The proposal would provide a new dimension to link substances of abuse, especially tobacco use and HIV-1, which is one of the major objectives of NIDA. In long term, this would provide an opportunity to develop novel therapeutic agents to treat HIV+ smokers effectively.

描述（由申请方提供）：吸烟对HIV感染的潜在影响可以从以下事实来衡量：HIV阳性人群的吸烟率估计为50-70%，而一般人群为20%。直到最近，人们才注意到吸烟与艾滋病毒1/艾滋病之间的潜在相互作用。吸烟及其主要成分尼古丁已被证明可增强肺泡巨噬细胞和小胶质细胞中的HIV-1复制，降低免疫反应，并降低对抗逆转录病毒治疗（ART）的反应。然而，人们对尼古丁引起这些效应的机制知之甚少。尼古丁及其主要代谢产物可替宁和其他重要的烟草特异性化合物主要由细胞色素P450 2A 6（CYP 2A 6）代谢，尤其是在肝脏中，以及由肺特异性CYP 2A 13代谢。这种代谢途径被认为会增加氧化应激和炎症，导致肝损伤，以及肺癌，食道癌和胰腺癌。包括我们在内的几项研究表明，CYP 2A 6在人单核细胞衍生的巨噬细胞中高度表达。我们的初步研究表明，CYP 2A 6在U937细胞系（巨噬细胞的HIV-1模型细胞系）中被尼古丁诱导。然而，其临床意义尚不清楚。巨噬细胞是HIV-1的主要细胞靶点之一，是重要的病毒库，也是HIV-1感染大脑的携带者（NeuroAIDS）。我们的目标是研究尼古丁在巨噬细胞中CYP 2A 6诱导的氧化应激和HIV-1复制中的作用。我们的假设是，尼古丁通过CYP 2A 6介导的尼古丁代谢和氧化应激增强巨噬细胞中的HIV-1复制。为了验证这一假设，本研究设计了两个具体目标。具体目的1：在人原代巨噬细胞中检查尼古丁对CYP 2A 6介导的氧化应激和HIV-1复制的作用。具体目标2：确定吸烟对HIV+吸烟者中CYP 2A 6表达、氧化应激和HIV-1复制的影响。成功完成本项目后，我们将验证我们的假设，即尼古丁通过CYP 2A 6介导的氧化应激在人巨噬细胞中增强HIV-1复制。这将首次提供尼古丁对巨噬细胞中HIV-1复制的影响及其发生机制的证据。这项新的工作将为HIV-1/尼古丁相关研究提供一个新的维度，并将为开发有效治疗HIV+吸烟者的新型治疗药物提供机会。 公共卫生相关性：该提案将研究吸烟/尼古丁对HIV-1复制中CYP 2A 6介导的氧化应激的作用。该提案将提供一个新的层面，将滥用药物，特别是烟草使用与艾滋病毒-1联系起来，这是NIDA的主要目标之一。从长远来看，这将为开发新的治疗药物以有效治疗HIV+吸烟者提供机会。