Molecular Virology Section, NIDDK, National Institutes of Health, Bethesda, Maryland, USA.
Cold Spring Harb Perspect Med. 2012 Jul;2(7):a006890. doi: 10.1101/cshperspect.a006890.
Retroviruses are distinguished from other viruses by two characteristic steps in the viral replication cycle. The first is reverse transcription, which results in the production of a double-stranded DNA copy of the viral RNA genome, and the second is integration, which results in covalent attachment of the DNA copy to host cell DNA. The initial catalytic steps of the integration reaction are performed by the virus-encoded integrase (IN) protein. The chemistry of the IN-mediated DNA breaking and joining steps is well worked out, and structures of IN-DNA complexes have now clarified how the overall complex assembles. Methods developed during these studies were adapted for identification of IN inhibitors, which received FDA approval for use in patients in 2007. At the chromosomal level, HIV integration is strongly favored in active transcription units, which may promote efficient viral gene expression after integration. HIV IN binds to the cellular factor LEDGF/p75, which promotes efficient infection and tethers IN to favored target sites. The HIV integration machinery must also interact with many additional host factors during infection, including nuclear trafficking and pore proteins during nuclear entry, histones during initial target capture, and DNA repair proteins during completion of the DNA joining steps. Models for some of the molecular mechanisms involved have been proposed, but important details remain to be clarified.
逆转录病毒通过病毒复制周期中的两个特征步骤与其他病毒区分开来。第一个是逆转录，导致病毒 RNA 基因组的双链 DNA 拷贝的产生，第二个是整合，导致 DNA 拷贝共价附着到宿主细胞 DNA 上。整合反应的初始催化步骤由病毒编码的整合酶 (IN) 蛋白完成。IN 介导的 DNA 断裂和连接步骤的化学性质已经得到很好的研究，并且 IN-DNA 复合物的结构现在已经阐明了整个复合物是如何组装的。在这些研究中开发的方法被用于鉴定 IN 抑制剂，这些抑制剂于 2007 年获得 FDA 批准用于患者。在染色体水平上，HIV 整合在活跃转录单元中受到强烈偏好，这可能促进整合后病毒基因的有效表达。HIV IN 与细胞因子 LEDGF/p75 结合，促进有效的感染，并将 IN 固定在优选的靶位上。HIV 整合机制在感染过程中还必须与许多其他宿主因子相互作用，包括核输入过程中的核转运和孔蛋白、初始靶标捕获过程中的组蛋白以及 DNA 连接步骤完成过程中的 DNA 修复蛋白。已经提出了一些涉及的分子机制的模型，但仍有重要细节需要澄清。
