MiRNA-mediated mechanisms of immune dysfunction in HIV patients

HIV患者免疫功能障碍的miRNA介导机制

• 批准号: 10223352
• 负责人: Francesca Peruzzi
• 金额: $ 19.94万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223352
• 关键词: AIDS related cancer; Affect; CD14 gene; CD4 Positive T Lymphocytes; Cells; Chronic; Development; Distant; Endotoxins; Failure; Functional disorder; Gene Expression; Gene Expression Profiling; Goals; HIV; HIV-1; Human Herpesvirus 8; Immune; Immune System Diseases; Immune response; Inflammation; Inflammatory; Inflammatory Response; Kaposi Sarcoma; Lead; Mediating; Messenger RNA; MicroRNAs; Molecular; Myeloid Cells; Oncology; Patients; Phenotype; Plasma; Play; Regulator Genes; Risk; Risk Factors; Role; Site; Untranslated RNA; Up-Regulation; Viral; cell transformation; exosome; immune activation; inflammatory milieu; macrophage; monocyte; prevent; recruit; tumor

The Human Immunodeficiency Virus 1 (HIV-1) mainly infect CD4+ T cells. It also infects myeloid cells, highly contributing to the chronic inflammation observed in HIV+ patients. Persistence of immune activation could lead to immune cell dysfunction and increased risk of developing HIV-associated malignancies, including Kaposi's Sarcoma (KS). Immune dysregulation and an inflammatory environment are risk factors for KS herpes virus (KSHV) reactivation and KS development. MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by inhibition or degradation of target mRNAs. MiRNAs are implicated in the macrophage maturation as well as their recruitment to inflammatory sites. In addition to their role as intracellular gene regulators, miRNAs can be secreted through exosomes and affect gene expression on recipient cells at distant sites. We isolated CD14+ cells from HIV subjects and healthy controls and polarized toward M1 and M2 phenotypes. Expression analysis of three pre-selected miRNAs revealed, as expected, a strong up-regulation of miR-155-Sp and miR-146a-5p during polarization of the controls cells; however, HIV-derived cells failed to upregulate these two miRNAs. Conversely, miR-223-3p, was more downregulated in macrophages derived from HIV patients compared to controls. As miR-146a and miR-155 play key roles in endotoxin tolerance (a transition state that prevents an excessive immune activation), failure to up-regulate those miRNAs by HIV-derived macrophages upon their activation may indicate a reduced ability of these cells to control inflammatory responses. Indeed, gene expression analysis of polarized macrophages revealed a dysfunctional immune response for both M 1 and M2 macrophages from HIV subjects compared to controls. In addition, we found dysregulated miRNAs in plasma exosomes from HIV subjects with or without KS. We hypothesize that dysregulated miRNA expression in circulating monocytes and exosomes in HIV +-subjects leads to dysfunctional macrophages, contributing to an inflammatory environment and tumor development.

人类免疫缺陷病毒1（HIV-1）主要感染CD 4 + T细胞。它还感染骨髓细胞，高度有助于在HIV+患者中观察到的慢性炎症。免疫激活的持续可能导致免疫细胞功能障碍，并增加发展HIV相关恶性肿瘤的风险，包括卡波西肉瘤（KS）。免疫失调和炎症环境是KS疱疹病毒（KSHV）再激活和KS发展的危险因素。MicroRNA（miRNAs）是一类短的非编码RNA，通过抑制或降解靶mRNA来调控基因表达。miRNA参与巨噬细胞成熟以及它们向炎症部位的募集。除了它们作为细胞内基因调节剂的作用之外，miRNA还可以通过外泌体分泌并影响受体细胞上远端位点的基因表达。我们从HIV受试者和健康对照中分离出CD 14+细胞，并向M1和M2表型极化。三种预先选择的miRNA的表达分析显示，正如预期的那样，在对照细胞的极化过程中，miR-155-Sp和miR-146 a-5 p强烈上调;然而，HIV衍生的细胞未能上调这两种miRNA。相反，与对照相比，miR-223- 3 p在来自HIV患者的巨噬细胞中下调更多。由于miR-146 a和miR-155在内毒素耐受性（防止过度免疫活化的过渡状态）中起关键作用，因此在HIV衍生的巨噬细胞活化时不能上调这些miRNA可能表明这些细胞控制炎症反应的能力降低。事实上，极化巨噬细胞的基因表达分析揭示了与对照相比，HIV受试者的M1和M2巨噬细胞的免疫应答功能障碍。此外，我们在有或没有KS的HIV受试者的血浆外泌体中发现了失调的miRNA。我们假设HIV +受试者中循环单核细胞和外泌体中的miRNA表达失调导致巨噬细胞功能失调，从而导致炎症环境和肿瘤发展。