HIV- induced long non-coding RNAs in viral replication and immune response

摘要 人类转录组的大部分由长的非编码RNA(LncRNAs)组成，它调节 蛋白质编码基因的表达和功能、免疫细胞的发育、分化和对 感染。LncRNAs在HIV感染细胞中的作用以及宿主lncRNAs如何影响复制和 艾滋病毒感染的持久性尚不清楚。这项建议目的是确定影响 病毒复制、对感染的细胞和免疫反应及其作用的分子机制。感染 诱导lncRNA表达的全球变化和病原体被认为影响免疫细胞功能 通过差异诱导调控的lncRNAs。我们的初步数据显示，在细胞内 HIV感染诱导的lncRNA表达。其中一些lncRNAs表现出显著的差异表达 在精英控制员的CD4+T细胞中，与慢性感染患者或未感染患者进行比较。我们 假设HIV感染通过不同的表达劫持宿主细胞和免疫机制 促进病毒复制的细胞内lncRNAs。我们将研究HIV诱导的lncRNA是否调节蛋白质- 编码基因和调节免疫反应(目标1)，并剖析艾滋病毒诱导的lncRNAs在病毒中的作用 复制(目标2)。我们将确定候选LncRNAs在精英中的显著差异表达 管制员有助于病毒抑制和免疫反应(目标3)。我们将通过一个 分子和生化技术与细胞模型的创新结合。此外，我们还将 描述新的lncRNAs的各种功能信息，如表达、细胞定位和 它们对蛋白质编码基因的影响。这项拟议的研究具有重要意义，因为它将确定 LncRNAs影响HIV复制，可作为治疗靶点。它还具有重要意义，因为它将 开发一个可扩展的平台来研究其他类型的宿主非编码RNA，并开辟新的途径 接受宿主指导的治疗。这项工作的预期结果是了解哪些lncRNA有助于 艾滋病病毒感染的临床结果。选举结果将产生重大影响，因为他们将建立一个更好的 了解lncRNAs在HIV感染和免疫应答中的作用，为进一步研究 治疗并最终根除艾滋病毒感染的干预措施。

Summary The majority of the human transcriptome consists of long non-coding RNAs (lncRNAs), which regulate the expression and function of protein-coding genes, immune cell development, differentiation, and response to infections. The role of lncRNAs in HIV-infected cells and how the host lncRNAs impact the replication and persistence of HIV infection is not known. The objective of this proposal is to identify host lncRNAs that influence viral replication, cellular and immune responses to infection and molecular mechanisms of their action. Infections induce global changes in lncRNA expression and pathogens are believed to impact immune cell functions through differential induction of regulatory lncRNAs. Our preliminary data showed significant changes in cellular lncRNA expression induced by HIV infection. Several of these lncRNAs showed significant differential expression in CD4+T cells from elite controllers as compared to chronically infected patients or uninfected individuals. We hypothesize that HIV infection hijacks host cellular and immune machinery through differential expression of cellular lncRNAs for facilitating virus replication. We will investigate if the HIV-induced lncRNAs regulate protein- coding genes and modulate the immune response (Aim 1) and dissect the role of HIV-induced lncRNAs in viral replication (Aim 2). We will determine if the significant differential expression of candidate lncRNAs in elite controllers contributes to viral inhibition and immune responses (Aim 3). We will pursue these aims using an innovative combination of molecular and biochemical techniques and cellular models. In addition, we will describe a wide variety of functional information for novel lncRNAs, such as expression, cellular localization and their influence of protein-coding genes. The proposed research is significant because it will determine which host lncRNAs impact HIV replication and could be used as therapeutic targets. It is also significant because it will develop a platform that can be extended to study other types of host non-coding RNAs and open new avenues for host-directed therapy. The expected outcome of this work is an understanding of which lncRNAs contribute to clinical outcomes of HIV infection. The results will have a significant impact because they will establish a better understanding of lncRNAs in HIV infection and immune response and lay the groundwork for development of interventions to treat and eventually eradicate HIV infection.