MiR-1236抑制VprBP翻译调节HIV-1复制研究及HIV-1感染后长期不发病中国人群基因多态性分析

发布时间：2018-12-15 06:03

【摘要】：本论文包括两部分内容： 1）MiR-1236抑制VprBP翻译调节HIV-1复制研究。单核细胞不易被HIV-1所感染，但当其分化成树突状细胞或巨噬细胞后易于被HIV-1感染。多种机制参与调控HIV-1在单核细胞中感染的限制性。细胞内miRNA能通过靶向结合HIV-1基因组或宿主基因转录本来调控HIV-1感染。在本工作中，我们分析了单核细胞和树突状细胞中基因和miRNA表达谱，发现宿主蛋白VprBP（HIV-1Vpr结合蛋白）的转录产物在单核细胞中被miR-1236所抑制，从而促进了单核细胞对HIV-1的限制。向单核细胞中转染miR-1236的抑制剂促进VprBP的翻译，，显著提高了病毒感染。树突状细胞中转入的外源人工合成miR-1236模拟物抑制了VprBP的翻译，相应地，显著降低了病毒感染。我们的结果强调了miRNA调控宿主细胞对HIV-1感染分化依赖的限制性作用。理解宿主miRNA对HIV-1感染的调控作用有助于鉴定新的抗病毒蛋白靶标以及发展新的抗病毒策略。 2）HIV-1感染后长期不发病中国人群基因多态性分析。少部分人感染HIV-1很长时间（10年）后在不经过治疗的情况下也不会发展成为艾滋病，我们将这部分人称作长期不发病病人（long-term non-progressors，LTNP）。病毒，免疫和宿主遗传因素之间的相互影响介导了这一表型。阐述清楚关键的调控疾病的宿主遗传因子有助于找到控制HIV-1的方法。我们通过外显子捕获测序分析了LTNP和AIDS中宿主基因之间的遗传差异。发现在LTNP和AIDS中众多单核苷酸多态性（single mucleotide polymorphisms，SNP）存在差异，其中一些SNP所在的基因与免疫或HIV-1调控有关。这些SNP在HIV-1控制和AIDS疾病进程中的确切作用有待后续实验分析探讨。
[Abstract]:This thesis consists of two parts: 1) MiR-1236 inhibits VprBP translation and regulates HIV-1 replication. Monocytes are not susceptible to HIV-1 infection, but are susceptible to HIV-1 infection when they differentiate into dendritic cells or macrophages. Several mechanisms are involved in regulating the restriction of HIV-1 infection in monocytes. Intracellular miRNA can regulate HIV-1 infection by targeting HIV-1 genome or host gene transcription. In this work, we analyzed the expression profiles of genes and miRNA in monocytes and dendritic cells. We found that the transcription products of host protein VprBP (HIV-1Vpr binding protein) were inhibited by miR-1236 in monocytes. This promotes the restriction of monocytes on HIV-1. Transfection of miR-1236 into monocytes promoted VprBP translation and significantly increased viral infection. Exogenous synthetic miR-1236 mimics in dendritic cells inhibited the translation of VprBP and significantly reduced viral infection. Our results emphasize the restrictive role of miRNA in regulating the differentiation dependence of host cells on HIV-1 infection. Understanding the role of host miRNA in the regulation of HIV-1 infection is helpful to identify new antiviral protein targets and to develop new antiviral strategies. 2) Polymorphism analysis of Chinese population after HIV-1 infection. A small number of people who have been infected with HIV-1 for a long time (10 years) do not develop AIDS without treatment, and we call this part of the population long term non-diseased patients (long-term non-progressors,LTNP). The interaction of virus, immune and host genetic factors mediates this phenotype. A clear understanding of the key host genetic factors that regulate disease is helpful in finding a way to control HIV-1. We analyzed the genetic differences between host genes in LTNP and AIDS by exon capture and sequencing. It was found that there were differences in many single nucleotide polymorphisms (single mucleotide polymorphisms,SNP) between LTNP and AIDS, and some of the SNP genes were related to immune or HIV-1 regulation. The exact role of these SNP in the control of HIV-1 and the progression of AIDS disease needs further experimental analysis.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R512.91

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