Revealing the RNA-RNA interactome of the HIV-1 genome

项目摘要/摘要 逆转录病毒和许多rna病毒一样，具有很高的突变率，使得快速的基因组进化可以选择 有益的宿主因素相互作用。近年来非编码RNA(NcRNAs)对宿主抗病毒作用的重要性 已经强调了过程；然而，许多rna病毒也进化到利用宿主ncRNAs。 为了他们自己的利益。事实上，已经确定了几种抑制复制的microRNAs(MiRNAs) 哺乳动物的RNA病毒，而其他的则会增加复制。需要指出的是，受抑制的复制 在许多情况下可能对病毒有利。此外，逆转录病毒依赖于宿主。 TRNA将它们的基因组RNA(GRNA)反转录成双链前病毒DNA。这 在逆转录病毒感染的过程中，基本的tRNA-gRNA相互作用先于所有酶催化的过程 宿主细胞。此外，由tRNAs内切产生的tRNA衍生片段(TRFs)具有 最近发现通过调节逆转录抑制内源性逆转录病毒的复制。由于 HIV-1对选择压力的快速反应，它可能已经进化出对RNA的反应机制- 介导的宿主过程；然而，对HIV-1gRNA核酸相互作用组的全面鉴定是 缺乏。在这里，我们的目标是测试HIV-1gRNA已经进化出关键的rna-rna这一最重要的假设。 交替构象、分子内远程相互作用和宿主直接结合等相互作用 NcRNAs，以优化传染性。其具体目的是(1)鉴定HIV-1gRNA分子内碱基配对和 分子间宿主RNA相互作用和(2)检测HIV-1RNA-RNA相互作用的生物学意义。

Project Summary/Abstract Retroviruses, like many RNA viruses, have high mutation rates, allowing rapid genome evolution to select for beneficial host factor interactions. Recently the importance of non-coding RNAs (ncRNAs) for host antiviral processes have been highlighted; however, many RNA viruses have also evolved to make use of host ncRNAs for their own benefit. Indeed, several microRNAs (miRNAs) have been identified that inhibit replication of mammalian RNA viruses while others increase replication. It is important to point out that repressed replication is likely to be advantageous to the virus in many instances. Furthermore, retroviruses are dependent on a host tRNA to prime reverse transcription of their genomic RNA (gRNA) into double-stranded proviral DNA. This fundamental tRNA-gRNA interaction precedes all enzyme-catalyzed processes during retroviral infection of a host cell. In addition, tRNA-derived fragments (tRFs) that result from endonucleolytic cleavage of tRNAs have recently been shown to inhibit endogenous retroviral replication by regulating reverse transcription. Due to the rapid response of HIV-1 to selective pressure, it is likely to have evolved mechanisms of responding to RNA- mediated host processes; however, comprehensive identification of the HIV-1 gRNA nucleic acid interactome is lacking. Here, we aim to test the overarching hypothesis that HIV-1 gRNA has evolved critical RNA-RNA interactions such as alternative conformations, long-range intra-molecular interactions and direct binding of host ncRNAs to optimize infectivity. The specific aims are to (1) identify HIV-1 gRNA intra-molecular base-pairing and inter-molecular host RNA interactions and (2) test the biological significance of HIV-1 RNA-RNA interactions.