Opioid Impact on Trim37-Induced Restriction of HIV

阿片类药物对 Trim37 诱导的 HIV 限制的影响

基本信息

批准号：
8314104
负责人：
Lauren Brittany Beach
金额：
$ 4.22万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-30 至 2014-08-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8314104
关键词：
Acquired Immunodeficiency Syndrome Affect Anti-Retroviral Agents Binding Biological Assay California Cattle Cell Line Cells Cercopithecus pygerythrus Co-Immunoprecipitations Cytokine Receptors DNA DNA biosynthesis Dendritic Cells Development Drug Addiction Drug user Enhancers Equus caballus Family member Felis catus Future Genetic Transcription Glioblastoma HIV HIV-1 Health Human Human Cell Line Immune Immune response Immune system Immunofluorescence Immunologic Infection Interferon Type I Interferons Laboratories Leukocytes Ligands Light Lipopolysaccharides Luciferases Macaca mulatta Messenger RNA Monitor Morphine Mus NF-kappa B NFAB complex Night Monkey Nuclear Opioid Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Process Proteins Publishing Receptor Signaling Relative (related person)Reporter Research Reverse Transcription Signal Transduction TNF Receptor-Associated Factors TRAF2 gene TRAF6 gene TRIM Motif Testing Tissue Sample Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha United States Virus Virus Diseases Virus Replication Withdrawal base cell type cytokine expression vector human TNF protein improved in vivo insight knock-down mu opioid receptors novel particle receptor receptor expression research study toll-like receptor 4 transcription factor viral DNA

项目摘要

This application proposes to investigate how Trim37, as a hypothesized component of the human innate immune system, influences HIV-1 replication dynamics in the presence or absence of opiods. Published research from several independent laboratories has revealed that opiods increase HIV replication ex vivo in human immune cells and in vivo in mice and rhesus macaques. It has been hypothesized that the mechanism for the observed increases in HIV-1 replication is due to opioids' well-documented ability to modulate cytokine and cytokine receptor signaling and expression. One recent study with murine dendritic cells has shown that the mu-opioid receptor, which is the receptor responsible for morphine's drug-induced effects, can be induced by the toll-like receptor 4 ligand, lipopolysaccharide (LPS). Unpublished research in the Mansky lab has demonstrated that Trim 37 is packaged into HIV-1 particles and decreases virus infectivity by reducing viral DNA synthesis. It has been previously observed that the expression of Trim37 results in the inability of TRAF proteins 2 and 6 to stimulate NF-KB binding to DNA. Notably, NF-KB is one of the major human transcription factors that transcribes HIV-1; tumor necrosis factor alpha (TNFalpha) and LPS both stimulate NF-KB's binding to DNA. This proposal seeks to determine whether various mammalian Trim37 proteins can also restrict HIV-1 infectivity in cell lines and primary cells. Both single-cycle replication and spreading HIV-1 infection assays will be performed in the presence of varying amounts of Trim37 to determine each Trim37 protein's antiretroviral effect. Due to the observations that both Trim37 and opioids can modulate NF-KB signaling, experiments will also be conducted in the presence of opioids. Additionally, experiments to determine whether Trim37's expression or localization changes in the presence of opioids, interferons I, II, and III, and TNFalpha will also be done. The determination of whether opioids alter the ability of Trim 37 to restrict HIV replication could help yield insight into the restriction mechanisms involved. Given that many of the 33.4 million HIV-1 infected people worldwide use opioids, these studies have the potential to improve global human health among HIV-1 infected opioid users.

该应用建议研究TRIM37是人类免疫系统的假设组成部分如何影响HIV-1复制动力学在存在或不存在OPIOD的情况下。来自几个独立实验室的发表研究表明，Opiods在人类免疫细胞和小鼠和恒河猕猴中的体内和体内增加了HIV复制。已经假设，HIV-1复制中观察到的增加的机制是由于阿片类药物有充分证明的调节细胞因子和细胞因子受体信号传导和表达的能力。一项针对鼠树突状细胞的最新研究表明，MU-阿片受体是负责吗啡药物诱导作用的受体，可以由Toll样受体4配体脂多糖（LPS）诱导。曼斯基实验室中未发表的研究表明，将TRIM 37包装到HIV-1颗粒中，并通过减少病毒DNA合成来降低病毒感染。先前已经观察到TRIM37的表达导致TRAF蛋白2和6无法刺激NF-KB与DNA结合。值得注意的是，NF-KB是转录HIV-1的主要人类转录因子之一。肿瘤坏死因子α（TNFALPHA）和LPS都刺激NF-KB与DNA的结合。该建议旨在确定各种哺乳动物TRIM37蛋白是否还可以限制细胞系和原代细胞中的HIV-1感染性。单周期复制和扩散HIV-1感染测定法将在不同量的TRIM37的情况下进行，以确定每种TRIM37蛋白的抗逆转录病毒效应。由于观察到TRIM37和阿片类药物都可以调节NF-KB信号传导，因此在存在阿片类药物的情况下也将进行实验。此外，还将完成在阿片类药物，干扰素I，II和III和TNFALPHA的存在中确定TRIM37表达或定位的实验。阿片类药物的确定是否改变了修剪37限制HIV复制的能力，可以帮助您深入了解所涉及的限制机制。鉴于全球3340万HIV-1感染的人中有许多阿片类药物，这些研究有可能改善HIV-1感染的阿片类药物使用者的全球人类健康。