Monocytic and exosomal cytochrome P450s in smoking-mediated HIV-1 pathogenesis

单核细胞和外泌体细胞色素 P450 在吸烟介导的 HIV-1 发病机制中的作用

• 批准号: 10203900
• 负责人: Theodore Cory
• 金额: $ 34.2万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203900
• 关键词: Adherence; Antioxidants; Blood specimen; Brain; CYP3A4 gene; Cells; Chemicals; Consumption; Cytochrome P450; Cytochromes; Data; Development; Disease; Enzymes; Goals; HIV; HIV therapy; HIV-1; Hepatic; In Vitro; Knowledge; Literature; Liver; Lung; Mediating; Messenger RNA; Metabolism; MicroRNAs; Microglia; Outcome; Oxidative Stress; Oxidative Stress Pathway; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Play; Population; Proteins; Publishing; Reporting; Role; Sampling; Site; Small Interfering RNA; Smoke; Smoker; Smoking; Substance of Abuse; Testing; Therapeutic; Tobacco; Tobacco smoking behavior; Toxic effect; Treatment Efficacy; Treatment outcome; Validation; Virus; Virus Replication; Work; antiretroviral therapy; base; cancer therapy; drug metabolism; effective therapy; exosome; improved; ineffective therapies; inhibitor/antagonist; macrophage; monocyte; nanovesicle; neuroAIDS; new therapeutic target; non-smoker; novel; novel therapeutic intervention; potential biomarker; recruit; replication therapy; response; success; therapy outcome; translational impact

Despite the success of antiretroviral therapy (ART), effective treatment outcomes among people with HIV-1 occur in only 1/3rd of the total HIV-1-population who receives treatment. In addition to reduced adherence to ART treatment, consumption of substance of abuse including tobacco smoking, which is highly prevalent in people with HIV-1, is one of the major factors for ineffective treatment outcomes. Smoking is known to exacerbate HIV- 1 pathogenesis in monocytes and macrophages, which serve as sanctuary sites for HIV-1 and infiltrate the brain, spreading the virus to perivascular macrophages and microglia and causing development of neuroAIDS. It is difficult to eliminate the virus in macrophages by ART. In addition, smoking accelerates HIV-1 replication, in part via increased oxidative stress. Our objective is to determine the role of monocytic and plasma exosomal CYP enzymes in enhancing smoking-mediated HIV-1 replication in smokers. We will accomplish our objective by testing the hypotheses that: 1) monocytic CYP enzymes mediate enhanced HIV-1 replication in smokers by contributing to increased oxidative stress and decreased ART efficacy and 2) circulating plasma exosomal CYP enzymes, secreted from liver and lung cells, are induced in smokers and delivered to macrophages contributing to enhanced HIV-1 replication. The rationale for the hypothesis is based on literature reports that smoking exacerbates HIV-1 replication in macrophages. Our own studies suggest that CYP enzymes are induced by tobacco smoking in monocytes and perhaps in plasma exosomes, and play a critical role in oxidative stress and ART metabolism in macrophages. We plan to test the hypotheses by determining the: Aim 1: Contribution of monocytic CYP enzymes in tobacco-enhanced HIV-1 replication in macrophages; Aim 2: Ex vivo validation of the role of CYP enzymes in smoking-enhanced HIV-1 replication; Aim 3: Contribution of plasma exosomal CYP enzymes to HIV-1 replication in macrophages. Upon completion of this project, we expect to determine the mechanistic contributions and gain a new understanding of a novel role of monocytic and plasma exosomal CYP enzymes in smoking-mediated HIV-1 pathogenesis. Thus, the project would impact the treatment of HIV-1 who smoke by providing a new target for novel therapeutic interventions, and potential application of exosomes as therapeutic carriers in effectively treating these patients.

尽管抗逆转录病毒疗法(Art)取得了成功，但hiv-1感染者的有效治疗结果仍然存在。 只有1/3的HIV-1感染者接受治疗。除了减少对ART的坚持之外 治疗、消费滥用物质，包括吸烟，这在人们中非常普遍 感染艾滋病毒-1是导致治疗效果不佳的主要因素之一。众所周知，吸烟会加剧艾滋病毒-- 1单核细胞和巨噬细胞的发病机制，单核细胞和巨噬细胞是HIV-1的避难所，并渗透到大脑， 将病毒传播到血管周围巨噬细胞和小胶质细胞，并导致神经艾滋病的发展。它是 用抗逆转录病毒技术难以清除巨噬细胞中的病毒。此外，吸烟在一定程度上加速了HIV-1的复制 通过增加氧化应激。我们的目标是确定单核细胞和血浆外体CYP的作用 促进吸烟导致吸烟者体内HIV-1复制的酶。我们将通过以下方式实现我们的目标 检验假设：1)单核细胞CYP酶通过以下方式介导吸烟者HIV-1复制的增强 导致氧化应激增加和ART疗效降低；2)循环血浆外体CYP 从肝脏和肺细胞分泌的酶在吸烟者体内被诱导，并被传递给巨噬细胞 到增强HIV-1复制。这一假设的理论基础是基于文献报道，即吸烟 会加剧巨噬细胞中HIV-1的复制。我们自己的研究表明，CYP酶是由 吸烟在单核细胞中，也可能在血浆外体中，并在氧化应激和 巨噬细胞中的ART代谢。我们计划通过确定以下各项来检验假设：目标1：贡献 烟草促进巨噬细胞中HIV-1复制的单核细胞CYP酶；目标2：体外验证 CYP酶在吸烟促进HIV-1复制中的作用；目标3：血浆外体CYP的作用 巨噬细胞中的酶对HIV-1复制的影响。在这个项目完成后，我们预计将确定 对单核细胞和血浆胞外体CYP新作用的新认识 吸烟与HIV-1致病机制中的酶。因此，该项目将影响艾滋病毒-1世卫组织的治疗。 通过为新的治疗干预提供新的靶点来吸烟，并潜在地应用外切体作为 有效治疗这些患者的治疗载体。