Effect of cellular microRNAs on HIV-1 replication

主要研究者：Zhang，Hui授权号：1 RO 1AI 078812 - 01 A2授权题目：细胞microRNAs对HIV-1复制的影响 修订摘要部分 microRNAs（miRNAs）是一类长度约为21 nt的调控RNA，具有抑制蛋白质翻译的功能。它们参与调节许多真核生物谱系中的各种生物学功能，包括植物、昆虫、脊椎动物和哺乳动物。越来越多的证据表明，人类免疫缺陷病毒1型（HIV-1）的复制受细胞或病毒衍生的miRNA的调控。最近，我们发现几种细胞miRNAs参与建立和维持HIV-1潜伏在静止的初级CD 4 T淋巴细胞。各种HIV-1 mRNA的3 '末端是一簇细胞miRNA的结合位点，包括mir-28、mir-125 b、mir-150、mir-223和mir-382，其在静息的CD 4 + T细胞中而不是在活化的CD 4+细胞中富集。这些miRNA的反义抑制剂可以显著抵消其相应的miRNA对用HIV-1感染性克隆转染的静息CD 4 T细胞中的HIV-1蛋白翻译或从接受抑制性高效抗逆转录病毒治疗（HAART）的HIV-1感染个体分离的静息CD 4 + T细胞的HIV-1产生的抑制作用。此外，我们还发现病毒粒子相关的细胞miRNA在HIV-1复制中可能发挥作用。由于miRNAs影响HIV-1复制的证据确凿，我们想提出以下项目来系统地研究细胞miRNAs对HIV-1复制的影响：（1）。进一步阐明细胞miRNA如何促进HIV-1在静息CD 4 T淋巴细胞中整合后潜伏期的机制研究（2）。进一步研究细胞miRNA与达特或Rev的低效表达之间的相互作用及其对静息CD 4 T淋巴细胞中HIV-1潜伏期的可能协同作用。该提案中的实验旨在详细了解细胞miRNA如何影响HIV-1复制的机制。这些信息对于进一步利用miRNA操纵在控制HIV-1复制和传播中的相关性至关重要。以下是两年期ARRA奖的修订目标，随后是两年期NIAID奖。

PI: Zhang, Hui Grant Number: 1RO1AI078812-01A2 Grant title: Effect of cellular microRNAs on HIV-1 replication Revised Abstract Section MicroRNAs (miRNAs) are short ~21-nt-long regulatory RNAs with the ability to repress protein translation. They are involved in the regulation of various biological functions in numerous eukaryotic lineages, including plants, insects, vertebrate, and mammals. Accumulating evidence has indicated that human immunodeficiency virus type 1 (HIV-1) replication is regulated by cellor virus-derived miRNAs. Recently, we have found that several cellular miRNAs are involved in establishing and maintaining HIV-1 latency in resting primary CD4 T-lymphocytes. The 3'termini of various HIV-1 mRNAs are the binding site of a cluster of cellular miRNAs including mir-28, mir-125b, mir-150, mir-223, and mir-382, which is enriched in the resting CD4+ T cells rather than in activated CD4+ cells. The antisense inhibitors of these miRNAs can significantly counteract the inhibitory effects of their corresponding miRNAs upon either HIV-1 protein translation in the resting CD4 T-cells transfected with HIV-1 infectious clone, or HIV-1 production from the resting CD4+ T-cells isolated from HIV-1-infected individuals receiving suppressive highly active antiretroviral treatment (HAART). Besides, we have also found that virion associated cellular miRNA could play a role in HIV-1 replication. As the evidence that miRNAs affect HIV-1 replication is solid, we would like to propose the following projects to systematically examine the effect of cellular miRNAs on HIV-1 replication: (1). Mechanistic studies to further clarify how cellular miRNAs contribute to HIV-1 postintegration latency in resting CD4 T-lymphocytes (2). Further investigate the interaction between cellular miRNAs and the inefficient expression of Tat or Rev and their possible synergetic contribution to HIV-1 latency in resting CD4 T-lymphocytes. Experiments in this proposal are designed to provide a detail understanding of the mechanism how cellular miRNAs affect HIV-1 replication. Such information is crucial for further exploiting the relevance of miRNA manipulation in controlling HIV-1 replication and transmission. Following revised aims are proposed for the 2-year ARRA award, which will be followed by a 2-year NIAID award.