Opioids, LPS and HIV

阿片类药物、脂多糖和艾滋病毒

• 批准号: 8848264
• 负责人: WENZHE HO
• 金额: $ 0.59万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848264
• 关键词: Address; Area; Astrocytes; Bacterial Translocation; Blood; CD4 Positive T Lymphocytes; Cell Wall; Cells; Chinese People; Chronic; Disease; Drug usage; Gene Expression; Genes; Gram-Negative Bacteria; HIV; HIV Infections; HIV-1; Health; Heroin; Heroin Users; Immune; Immune Targeting; In Vitro; Infection; Injury; Interferons; Lipopolysaccharides; Measures; Mediating; MicroRNAs; Microglia; Molecular; Molecular Profiling; Morphine; Natural Immunity; Neuraxis; Neurons; Opioid; Pathogenesis; Pathway interactions; Plasma; Predisposition; Reporting; Role; Series; Substance abuse problem; System; base; cofactor; immune activation; in vivo; innovation; interest; lipopolysaccharide-binding protein; macrophage; monocyte; novel; opioid abuse

DESCRIPTION (provided by applicant): While it is known that opioids exert a profound influence on immunomodulating activity and have a cofactor role in the immunopathogenesis of HIV-1 disease, the mechanism(s) of their action remains to be determined. There is little information available about the association of opioid use with elevated plasma levels of lipopolysaccharide (LPS), a major component of gram-negative bacteria cell walls and a likely cause of systemic immune activation in HIV infection [1]. Particularly, it is unknown about the effect of opioid use in the presence of LPS on cellular microRNA and gene expression in HIV-1-targeted immune cells such as CD4+ T cells, monocytes, and microglia. Thus, to determine changes of miRNAs and genes related HIV infection of CD4+ T cells, monocytes, and microglia exposed to opioids is the area of interest, which may help to identify previously unidentified mechanisms involved in pathogenesis of HIV disease. The rationale of this proposal is based on the recent reports, showing that increased levels of plasma LPS in the blood is a consequence of translocation of bacterial products from a leaky gut, which is likely responsible for the systemic immune activation in chronic HIV infection [1] and that substance abuse is associated with high plasma LPS [2]. In addition, it has been recently documented that intracellular anti-HIV cellular factors in CD4+ T cells and monocytes/macrophages have a critical role in suppression of HIV infection/replication [3, 4]. Therefore, we hypothesize that drugs of use such as heroin is associated with elevated plasma levels of LPS and that opioids (heroin or morphine) suppress intracellular anti- HIV innate immunity in the immune cells and CNS cells, promoting HIV infection. We propose three specific aims to address previously unrecognized impact and mechanisms by which opioids and /or LPS compromise host cell innate immunity, increasing the susceptibility of immune and the CNS cells to HIV-1 infection and injury. In aim 1, we will examine in vivo impact of heroin use on the expression of markers of microtranslocation as well as on miRNA/gene profile of CD4+ T cells and monocytes with focus on the JAK/STAT pathways. In aim 2, we will examine in vitro impact of morphine and/or LPS on the expression of miRNA profiles with focus on newly identified anti-HIV miRNAs in CD4+ T cells, monocytes and macrophages. We will determine the molecular mechanisms responsible for morphine/LPS-mediated actions on intracellular innate immunity and HIV infection. In aim 3, we will determine the impact of opioids and/or LPS on the expression of anti-HIV miRNAs in astrocytes and microglia. We hypothesize that morphine and/or LPS, through the suppression of innate immunity in the CNS cells (primary astrocytes, microgila, and neurons), increase the susceptibility of microglia and astrocytes to HIV infection. The proposed studies are highly significant and innovative, as we will address the novel questions of whether opioid use is positively associated elevated plasma LPS in Chinese heroin dependent subjects, and whether opioids and/or LPS suppress intracellular anti-HIV innate immunity in the immune and CNS cells, promoting HIV infection.

描述（由申请人提供）：虽然众所周知，阿片类药物对免疫调节活性产生了深远的影响，并且在HIV-1疾病的免疫发病中具有辅助作用，但其作用的机制仍有待确定。关于阿片类药物使用与血浆水平升高的脂多糖（LPS）的关联，革兰氏阴性细菌细胞壁的主要成分以及HIV感染中系统性免疫激活的可能原因[1]。特别是，在HIV-1靶向的免疫细胞（例如CD4+ T细胞，单核细胞和小胶质细胞）中，在LPS存在阿片类药物使用对细胞microRNA和基因表达的影响尚不清楚。因此，为了确定miRNA和基因与CD4+ T细胞，单核细胞和暴露于阿片类药物的小胶质细胞的HIV感染的变化是感兴趣的领域，这可能有助于确定先前未识别的HIV病发病机理。该提案的基本原理是基于最近的报道，表明血液中血浆LPS的水平升高是由于肠道渗漏的细菌产物易位的结果，这可能导致慢性HIV感染的全身免疫激活[1]，而该药物滥用滥用与高血浆LPS相关[2]。此外，最近已有记录，CD4+ T细胞和单核细胞/巨噬细胞中细胞内抗HIV细胞因子在抑制HIV感染/复制方面具有关键作用[3，4]。因此，我们假设使用药物（例如海洛因）与血浆LPS的升高有关，而阿片类药物（海洛因或吗啡）抑制了免疫细胞和CNS细胞中细胞内抗HIV先天性免疫，从而促进HIV感染。我们提出了三个特定的目的，旨在解决阿片类药物和 /或LPS损害宿主细胞先天免疫，增加免疫和中枢神经系统细胞对HIV-1感染和损伤的敏感性，从而解决先前无法识别的影响和机制。在AIM 1中，我们将检查使用海洛因对微递归标记以及CD4+ T细胞和单核细胞的miRNA/基因谱的表达的体内影响，侧重于JAK/STAT途径。在AIM 2中，我们将检查吗啡和/或LP对miRNA谱的表达的体外影响，重点是在CD4+ T细胞，单核细胞和巨噬细胞中新鉴定的抗HIV miRNA。我们将确定负责吗啡/LPS介导的作用对细胞内先天免疫和HIV感染的作用的分子机制。在AIM 3中，我们将确定阿片类药物和/或LP对星形胶质细胞和小胶质细胞中抗HIV miRNA的表达的影响。我们假设吗啡和/或LPS通过抑制CNS细胞（主要星形胶质细胞，小胶质细胞和神经元）中的先天免疫力，增加了小胶质细胞和星形胶质细胞对HIV感染的敏感性。拟议的研究具有非常重要和创新性的，因为我们将解决中国海洛因依赖性受试者中使用阿片类药物是否呈正相关的血浆LPS的新颖问题，以及阿片类药物和/或LPS是否抑制细胞内的抗HIV抗HIV抗HIV抗HIV先天性免疫细胞中的免疫和CNS细胞，从而促进HIV感染。