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 Unpublished research in the Mansky lab has demonstrated that Trim 37 is packaged into HIV-1 particles and decreases virus infectivity by reducing viral DNA synthesis.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）：本申请提出研究Trim 37作为人类先天免疫系统的假设组分，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中以及在小鼠和恒河猴体内增加HIV复制。据推测，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传导和表达的能力得到了充分证实。最近一项对鼠树突状细胞的研究表明，μ-阿片受体（负责吗啡药物诱导作用的受体）可以被toll样受体4配体脂多糖（LPS）诱导。Mansky实验室未发表的研究表明，Trim 37被包装到HIV-1颗粒中，并通过减少病毒DNA合成来降低病毒感染性。先前已经观察到Trim 37的表达导致TRAF蛋白2和6不能刺激NF-κ B与DNA结合。值得注意的是，NF-κ B是转录HIV-1的主要人类转录因子之一;肿瘤坏死因子α（TNF α）和LPS都刺激NF-κ B与DNA的结合。该提案旨在确定各种哺乳动物Trim 37蛋白是否也可以限制细胞系和原代细胞中的HIV-1感染性。将在存在不同量的Trim 37的情况下进行单循环复制和传播HIV-1感染测定，以确定每种Trim 37蛋白的抗逆转录病毒作用。由于观察到Trim 37和阿片样物质都可以调节NF-κ B信号传导，因此也将在阿片样物质存在下进行实验。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TNF α存在下Trim 37的表达或定位是否发生变化。确定阿片类药物是否改变Trim 37限制HIV复制的能力，可能有助于深入了解所涉及的限制机制。鉴于全球3340万HIV-1感染者中有许多人使用阿片类药物，这些研究有可能改善HIV-1感染阿片类药物使用者的全球人类健康。 公共卫生相关性：在美国，有110多万人感染了人体免疫缺陷病毒（艾滋病毒），这是艾滋病的病因，其中许多人是注射类阿片药物使用者。这项研究调查了Trim 37和阿片类药物对人类先天免疫系统的影响，它们对人类先天免疫应答对HIV感染的功能的机制贡献。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HIV-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。