Opioid Impact on Trim37-Induced Restriction of HIV

阿片类药物对 Trim37 诱导的 HIV 限制的影响

• 批准号: 8012215
• 负责人: Lauren Brittany Beach
• 金额: $ 4.14万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/8012215
• 关键词: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Binding; Biological Assay; Cell Line; Cells; Cytokine Receptors; DNA; DNA biosynthesis; Dendritic Cells; Development; Drug Addiction; Drug user; Future; HIV; HIV-1; Health; Human; Immune; Immune response; Immune system; Infection; Interferons; Laboratories; Ligands; Lipopolysaccharides; Macaca mulatta; Morphine; Mus; NF-kappa B; Opioid; Pharmaceutical Preparations; Proteins; Publishing; Receptor Signaling; Research; Signal Transduction; TNF Receptor-Associated Factors; Tumor Necrosis Factor-alpha; United States; Virus; Virus Diseases; Virus Replication; cytokine; improved; in vivo; insight; mu opioid receptors; novel; particle; public health relevance; receptor; research study; toll-like receptor 4; transcription factor; viral DNA

DESCRIPTION (provided by applicant): 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 Unpublished research in the Mansky lab has demonstrated that Trim 37 is packaged into HIV-1 particles and decreases virus infectivity by reducing viral DNA synthesis.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. PUBLIC HEALTH RELEVANCE: In the United States, over 1.1 million people, many of whom are injecting opioid drug users, are infected with the human immunodeficiency virus (HIV), the cause of AIDS. This study investigates the mechanistic contributions that Trim37 and opioids, both of which impact the human innate immune system, have on the function of the human innate immune response to HIV infection. These studies will result in a better understanding about how the innate immune system functions in the presence or absence of HIV-1 infection and/or opioid use, which could ultimately contribute to the future development of novel drugs to treat viral infections and opioid drug-addiction, thus advancing the improvement of human health worldwide.

描述(由申请人提供)：这项申请建议调查Trim37作为人类先天性免疫系统的一个假设组件，在存在或不存在阿片类药物的情况下如何影响HIV-1复制动力学。几个独立实验室发表的研究表明，阿片类药物在人体免疫细胞外以及在小鼠和猕猴体内都能增加艾滋病毒的复制。有人假设，观察到的HIV-1复制增加的机制是由于阿片类药物调节细胞因子和细胞因子受体信号和表达的能力。最近对小鼠树突状细胞的一项研究表明，Mu-阿片受体是负责吗啡药物诱导效应的受体，可以由Toll样受体4配体脂多糖(LPS)诱导。曼斯基实验室未发表的研究表明，TRIM 37被包装在HIV-1颗粒中，通过减少病毒DNA合成来降低病毒的传染性。先前观察到，Trim37的表达导致TRAF蛋白2和6不能刺激核因子-KB与DNA结合。值得注意的是，核因子-kB是人类转录HIV-1的主要转录因子之一；肿瘤坏死因子α和脂多糖都能刺激核因子-kB与DNA的结合。这项提议旨在确定哺乳动物的各种Trim37蛋白是否也可以限制HIV-1在细胞系和原代细胞中的传染性。将在不同数量的Trim37存在的情况下进行单周期复制和传播HIV-1感染分析，以确定每个Trim37蛋白的抗逆转录病毒效果。由于观察到Trim37和阿片类药物都可以调制NF-KB信号，因此也将在阿片类药物存在的情况下进行实验。此外，还将进行实验，以确定在阿片类药物、干扰素I、II和III以及肿瘤坏死因子α存在的情况下，Trim37‘S的表达或定位是否发生变化。确定阿片类药物是否改变了TRIM 37限制艾滋病毒复制的能力，可能有助于深入了解所涉及的限制机制。鉴于全世界3340万艾滋病毒-1感染者中的许多人使用阿片类药物，这些研究有可能改善感染艾滋病毒-1的阿片类药物使用者的全球人类健康。 与公共卫生相关：在美国，超过110万人感染了人类免疫缺陷病毒(HIV)，这是艾滋病的原因，其中许多人正在注射阿片类药物。这项研究调查了Trim37和阿片类药物对人类对HIV感染的先天免疫反应的作用机制，这两种药物都会影响人类的先天免疫系统。这些研究将有助于更好地了解先天免疫系统在存在或不存在艾滋病毒-1感染和/或阿片类药物使用的情况下如何发挥作用，这最终可能有助于未来开发治疗病毒感染和阿片类药物成瘾的新药，从而促进全球人类健康的改善。