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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

基本信息

批准号：
10439755
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439755
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 Persons 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 macrophage monocyte nanovesicle neuroAIDS new therapeutic target non-smoker novel novel therapeutic intervention potential biomarker recruit replication therapy response success therapy outcome translational impact

项目摘要

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，但在HIV-1感染者中，只有三分之一的HIV-1感染者接受治疗。除了减少对抗逆转录病毒疗法的坚持外，治疗，滥用物质的消费，包括吸烟，这是非常普遍的人感染HIV-1是治疗无效的主要因素之一。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，作为HIV-1的避难所并浸润大脑，将病毒传播到血管周围的巨噬细胞和小胶质细胞，并导致神经艾滋病的发展。是很难通过ART消除巨噬细胞中的病毒。此外，吸烟加速HIV-1复制，部分原因是通过增加氧化应激。我们的目的是确定单核细胞和血浆外泌体的作用，酶增强吸烟者吸烟介导的HIV-1复制。我们将通过以下方式实现我们的目标检验以下假设：1）单核细胞粘附酶介导吸烟者中HIV-1复制增强，导致氧化应激增加和ART功效降低，和2）循环血浆外泌体分泌增加，从肝和肺细胞分泌的酶，在吸烟者中被诱导并被递送到巨噬细胞，以增强HIV-1的复制。该假设的基本原理是基于文献报道，吸烟加剧了HIV-1在巨噬细胞中的复制。我们自己的研究表明，吸烟在单核细胞和可能在血浆外泌体中起重要作用，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目标来测试假设：目标1：烟草中的单核细胞粘附酶增强了巨噬细胞中HIV-1的复制;目的2：体外验证吸烟增强HIV-1复制中转录酶的作用;目的3：血浆外泌体转录酶的作用酶对HIV-1在巨噬细胞中复制的影响。在这个项目完成后，我们预计将确定机制的贡献，并获得一个新的作用，单核细胞和血浆外泌体的新的认识，吸烟介导的HIV-1发病机制中的酶。因此，该项目将影响HIV-1的治疗，通过为新的治疗干预提供新的靶点来吸烟，以及外泌体作为有效治疗这些患者的治疗载体。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The importance of targeting HIV reservoirs: preclinical insights on current and potential therapeutic opportunities.

针对艾滋病毒储存库的重要性：对当前和潜在治疗机会的临床前见解。

DOI：
10.1080/14728222.2019.1702971
发表时间：
2019
期刊：
Expert opinion on therapeutic targets
影响因子：
5.8
作者：
Cory,TheodoreJ
通讯作者：
Cory,TheodoreJ

Racial Health Disparity and COVID-19.

DOI：
10.1007/s11481-021-10014-7
发表时间：
2021-12
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
0
作者：
Kumar S;Kumar P;Kodidela S;Duhart B;Cernasev A;Nookala A;Kumar A;Singh UP;Bissler J
通讯作者：
Bissler J

Challenges in Biomaterial-Based Drug Delivery Approach for the Treatment of Neurodegenerative Diseases: Opportunities for Extracellular Vesicles.

DOI：
10.3390/ijms22010138
发表时间：
2020-12-25
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Kumar A;Zhou L;Zhi K;Raji B;Pernell S;Tadrous E;Kodidela S;Nookala A;Kochat H;Kumar S
通讯作者：
Kumar S

Intervention and Improved Well-Being of Basic Science Researchers During the COVID 19 Era: A Case Study.