Tobacco/nicotine, cytochrome P450, and HIV-1

描述（由申请人提供）：吸烟对艾滋病毒情景的潜在影响可以通过以下事实来衡量：艾滋病毒阳性人群的吸烟率估计为50-70%，而一般人群的吸烟率为20%。直到最近，很少有人注意到吸烟与HIV-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影响的机制知之甚少。尼古丁及其主要代谢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 2A6 （CYP2A6）代谢，特别是在肝脏，以及肺特异性CYP2A13。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，CYP2A6在人单核细胞来源的巨噬细胞中高度表达。我们的初步研究表明，尼古丁在U937细胞系（巨噬细胞的HIV-1模型细胞系）中诱导CYP2A6。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，是关键的病毒库，也是HIV-1感染到大脑的载体（NeuroAIDS）。我们的目标是研究尼古丁在巨噬细胞中cyp2a6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cyp2a6介导的尼古丁代谢和氧化应激增强巨噬细胞中HIV-1的复制。为了验证这一假设，本研究的设计有两个具体目的。特异性目的1：研究尼古丁在人原代巨噬细胞中cyp2a6介导的氧化应激和HIV-1复制中的作用。特异性目的2：确定吸烟对HIV+吸烟者CYP2A6表达、氧化应激和HIV-1复制的影响。在该项目成功完成后，我们将验证尼古丁通过cyp2a6介导的人巨噬细胞氧化应激增强HIV-1复制的假设。这将为尼古丁对巨噬细胞中HIV-1复制的影响及其发生机制提供第一个证据。这项新工作将为HIV-1/尼古丁相关研究提供一个新的维度，并为开发有效治疗HIV+吸烟者的新型治疗药物提供机会。

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.