Poeschla E M
Guggenheim 18, Mayo Clinic College of Medicine, 200 First Street SW, Rochester 55905, USA.
Cell Mol Life Sci. 2008 May;65(9):1403-24. doi: 10.1007/s00018-008-7540-5.
HIV integrates a DNA copy of its genome into a host cell chromosome in each replication cycle. The essential DNA cleaving and joining chemistry of integration is known, but there is less understanding of the process as it occurs in a cell, where two complex and dynamic macromolecular entities are joined: the viral pre-integration complex and chromatin. Among implicated cellular factors, much recent attention has coalesced around LEDGF/p75, a nuclear protein that may act as a chromatin docking factor or receptor for lentiviral pre-integration complexes. LEDGF/p75 tethers HIV integrase to chromatin, protects it from degradation, and strongly influences the genome-wide pattern of HIV integration. Depleting the protein from cells and/or over-expressing its integrase-binding domain blocks viral replication. Current goals are to establish the underlying mechanisms and to determine whether this knowledge can be exploited for antiviral therapy or for targeting lentiviral vector integration in human gene therapy.
在每个复制周期中，人类免疫缺陷病毒（HIV）会将其基因组的DNA拷贝整合到宿主细胞染色体中。整合过程中DNA切割和连接的关键化学过程已为人所知，但对于该过程在细胞内发生时的情况了解较少，因为在细胞中，两个复杂且动态的大分子实体被连接在一起：病毒前整合复合物和染色质。在涉及的细胞因子中，最近很多注意力都集中在LEDGF/p75上，它是一种核蛋白，可能作为染色质对接因子或慢病毒前整合复合物的受体。LEDGF/p75将HIV整合酶与染色质相连，保护其不被降解，并强烈影响HIV整合在全基因组范围内的模式。从细胞中耗尽该蛋白和/或过度表达其整合酶结合结构域会阻断病毒复制。当前的目标是确定潜在机制，并确定这一知识是否可用于抗病毒治疗或在人类基因治疗中靶向慢病毒载体整合。
