miR-198 inhibits HIV-1 gene expression and replication in monocytes and its mechanism of action appears to involve repression of cyclin T1.
miR-198 inhibits HIV-1 gene expression and replication in monocytes and its mechanism of action appears to involve repression of cyclin T1.
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DOI：
10.1371/journal.ppat.1000263
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发表时间：
2009-01
期刊：
影响因子：
6.7
通讯作者：
Rice, Andrew P.
中科院分区：
文献类型：
--
作者：
Sung, Tzu-Ling;Rice, Andrew P.
细胞周期蛋白T1是一种称为P-TEFb的RNA聚合酶II延伸因子的调节亚基。细胞周期蛋白T1也是达特反式激活HIV-1 LTR指导的基因表达所必需的。细胞周期蛋白T1 mRNA的翻译在人单核细胞中被抑制，当细胞分化为巨噬细胞时，这种抑制被解除。我们将miR-198鉴定为当单核细胞被诱导分化时强烈下调的microRNA（miRNA）。组织培养细胞中miR-198的异位表达降低了Cyclin T1蛋白的表达，质粒报告基因分析证实了miR-198靶序列位于Cyclin T1 mRNA的3′非翻译区（3′UTR）。当miR-198的抑制剂转染到原代单核细胞中时，Cyclin T1蛋白水平增加，并且原代单核细胞中miR-198的过表达抑制了分化期间Cyclin T1的正常上调。在miR-198过表达后，HIV-1前病毒质粒的表达和HIV-1复制在单核细胞系中受到抑制。我们的数据表明，miR-198的功能是限制HIV-1在单核细胞中的复制，其作用机制似乎涉及抑制细胞周期蛋白T1的表达。单核细胞不支持HIV-1复制，部分原因是它们不表达足够水平的介导病毒复制周期步骤的必需细胞辅因子。单核细胞在分化为巨噬细胞后变得允许病毒复制，表明细胞辅因子在分化过程中被诱导。一种这样的辅因子是细胞周期蛋白T1，其在单核细胞中不表达，并且在巨噬细胞分化后以高水平表达。细胞周期蛋白T1的功能是极大地刺激受感染细胞中产生的HIV-1的量。我们鉴定了一种名为miR-198的microRNA（miRNA），其抑制单核细胞中Cyclin T1的表达。miRNA通过与信使RNA结合并阻止它们被核糖体翻译来阻断蛋白质的表达。miR-198的表达水平在巨噬细胞中大大降低，这似乎允许Cyclin T1 mRNA的翻译和Cyclin T1蛋白的表达。我们的研究表明，这种miRNA限制了HIV-1在单核细胞中的复制。我们认为，单核细胞中额外的miRNA也可能通过抑制其他必需的细胞辅因子来限制HIV-1的复制。
Cyclin T1 is a regulatory subunit of a general RNA polymerase II elongation factor known as P-TEFb. Cyclin T1 is also required for Tat transactivation of HIV-1 LTR-directed gene expression. Translation of Cyclin T1 mRNA has been shown to be repressed in human monocytes, and this repression is relieved when cells differentiate to macrophages. We identified miR-198 as a microRNA (miRNA) that is strongly down-regulated when monocytes are induced to differentiate. Ectopic expression of miR-198 in tissue culture cells reduced Cyclin T1 protein expression, and plasmid reporter assays verified miR-198 target sequences in the 3′ untranslated region (3′UTR) of Cyclin T1 mRNA. Cyclin T1 protein levels increased when an inhibitor of miR-198 was transfected into primary monocytes, and overexpression of miR-198 in primary monocytes repressed the normal up-regulation of Cyclin T1 during differentiation. Expression of an HIV-1 proviral plasmid and HIV-1 replication were repressed in a monocytic cell line upon overexpression of miR-198. Our data indicate that miR-198 functions to restrict HIV-1 replication in monocytes, and its mechanism of action appears to involve repression of Cyclin T1 expression. Monocytes do not support HIV-1 replication, in part because they do not express adequate levels of essential cellular cofactors that mediate steps in the viral replication cycle. Monocytes become permissive for viral replication upon differentiation to macrophages, indicating that cellular cofactors are induced during the differentiation process. One such cofactor is Cyclin T1, which is not expressed in monocytes and is expressed at high levels following macrophage differentiation. Cyclin T1 functions to greatly stimulate the amount of HIV-1 produced in the infected cell. We identified a microRNA (miRNA) named miR-198 that represses the expression of Cyclin T1 in monocytes. miRNAs block expression of proteins by binding to messenger RNAs and preventing their translation by ribosomes. The expression levels of miR-198 are greatly reduced in macrophages, and this appears to allow translation of Cyclin T1 mRNA and expression of Cyclin T1 protein. Our study indicates that this miRNA restricts HIV-1 replication in monocytes. We think that it is possible, if not likely, that additional miRNAs in monocytes also restrict HIV-1 replication by repressing other essential cellular cofactors.
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