Grandgenett Duane P, Pandey Krishan K, Bera Sibes, Aihara Hideki
Duane P Grandgenett, Krishan K Pandey, Sibes Bera, Institute for Molecular Virology, Saint Louis University Health Sciences Center, St. Louis, MO 63104, United States.
World J Biol Chem. 2015 Aug 26;6(3):83-94. doi: 10.4331/wjbc.v6.i3.83.
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.
逆转录病毒整合酶（IN）负责将逆转录产生的线性cDNA整合到宿主DNA基因组中。首先，IN从病毒DNA的3' OH平端切割下一个二核苷酸，使凹陷末端暴露出高度保守的CA序列。IN利用3' OH末端催化两端协同整合到细胞DNA的相反链中，根据逆转录病毒的种类产生4至6个碱基对的交错插入。交错末端由宿主细胞机制修复，这导致病毒DNA在细胞基因组中永久复制。除了整合作用外，IN在几种已研究的逆转录病毒的复制周期中还发挥其他功能。IN在病毒内核中的正确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以及与病毒衣壳蛋白和一种细胞蛋白结合，在逆转录过程中发挥主要作用。IN还促进了几种其他宿主蛋白被招募到病毒颗粒中。IN协助整合前复合物穿过核膜进行核运输。对于几种逆转录病毒，IN与不同的宿主蛋白因子特异性相互作用，这些因子引导整合前复合物将病毒基因组优先整合到宿主染色体靶标的特定区域。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活性位点内，从而阻止整合及后续的HIV / AIDS。
