Multifunctional facets of retrovirus integrase.
Multifunctional facets of retrovirus integrase.
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DOI：
10.4331/wjbc.v6.i3.83
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发表时间：
2015-08-26
期刊：
影响因子：
--
通讯作者：
Aihara, Hideki
中科院分区：
文献类型：
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作者：
Grandgenett, Duane P;Pandey, Krishan K;Aihara, Hideki
逆转录病毒整合酶（IN）负责将逆转录的线性cDNA整合到宿主DNA基因组中。首先，IN从病毒DNA的3' OH平端切割二核苷酸，暴露凹陷端中的高度保守的CA序列。IN利用3' OH末端催化两个末端协同整合到细胞DNA的相对链中，产生4至6 bp交错插入，这取决于逆转录病毒种类。交错的末端被宿主细胞机制修复，导致细胞基因组中病毒DNA的永久拷贝。除了整合，IN在几种研究的逆转录病毒的复制周期中执行其他功能。IN在病毒内核内的适当组织对于病毒的正确成熟至关重要。IN通过直接与逆转录酶相互作用并通过结合病毒衣壳蛋白和细胞蛋白在逆转录中起主要作用。IN还促进了几种其他宿主蛋白向病毒颗粒中的募集。IN协助整合前复合物的核转运穿过核膜。对于几种逆转录病毒，IN特异性地与不同的宿主蛋白因子相互作用，所述宿主蛋白因子引导整合前复合物优先将病毒基因组整合到宿主染色体靶标的特定区域中。使用逆转录病毒载体的人类基因治疗直接受到IN与这些宿主因子的相互作用的影响。针对人类免疫缺陷病毒（HIV）IN的抑制剂结合在含有病毒DNA末端的IN的活性位点内，从而防止整合和随后的HIV/AIDS。
The retrovirus integrase (IN) is responsible for integration of the reverse transcribed linear cDNA into the host DNA genome. First, IN cleaves a dinucleotide from the 3' OH blunt ends of the viral DNA exposing the highly conserved CA sequence in the recessed ends. IN utilizes the 3' OH ends to catalyze the concerted integration of the two ends into opposite strands of the cellular DNA producing 4 to 6 bp staggered insertions, depending on the retrovirus species. The staggered ends are repaired by host cell machinery that results in a permanent copy of the viral DNA in the cellular genome. Besides integration, IN performs other functions in the replication cycle of several studied retroviruses. The proper organization of IN within the viral internal core is essential for the correct maturation of the virus. IN plays a major role in reverse transcription by interacting directly with the reverse transcriptase and by binding to the viral capsid protein and a cellular protein. Recruitment of several other host proteins into the viral particle are also promoted by IN. IN assists with the nuclear transport of the preintegration complex across the nuclear membrane. With several retroviruses, IN specifically interacts with different host protein factors that guide the preintegration complex to preferentially integrate the viral genome into specific regions of the host chromosomal target. Human gene therapy using retrovirus vectors is directly affected by the interactions of IN with these host factors. Inhibitors directed against the human immunodeficiency virus (HIV) IN bind within the active site of IN containing viral DNA ends thus preventing integration and subsequent HIV/AIDS.