Harland June, Dunn Paul, Cameron Euan, Conner Joe, Brown S Moira
Glasgow University, Neurovirology Research Laboratories, Institute of Neurological Sciences, Southern General Hospital, Glasgow, United Kingdom.
J Neurovirol. 2003 Aug;9(4):477-88. doi: 10.1080/13550280390218788.
The replicative ability of ICP34.5-null herpes simplex virus (HSV) is cell type and state dependent. In certain cells, ICP34.5 interacts with protein phosphatase 1 to preclude host cell protein synthesis shutoff by dephosphorylation of the eukaryotic initiation factor eIF-2alpha. However, host cell shutoff is not induced by ICP34.5-null HSV in most cells, irrespective of type and state. In general, dividing cells support replication of ICP34.5-null HSV; nondividing cells cannot. Previously the authors showed that ICP34.5 binds to proliferating cell nuclear antigen (PCNA), a protein necessary for cellular DNA replication and repair. Here the authors demonstrate that (1) the interaction between ICP34.5 and PCNA involves two regions of the virus protein; (2) ICP34.5 forms a complex with HSV replication proteins that is DNA binding; (3) at early times in infection, ICP34.5 colocalizes with PCNA and HSV replication proteins in cell nuclei, before accumulating in the cytoplasm; and (4) ICP34.5 is a virion protein. In light of ongoing clinical trials assessing the safety and efficacy of ICP34.5-null HSV, it is vital that the roles of ICP34.5 in HSV replication are understood. The authors propose that in nondividing cells, ICP34.5 is required to switch PCNA from repair to replication mode, a prerequisite for the initiation of HSV replication.
缺失 ICP34.5 的单纯疱疹病毒（HSV）的复制能力取决于细胞类型和状态。在某些细胞中，ICP34.5 与蛋白磷酸酶 1 相互作用，通过使真核起始因子 eIF-2α 去磷酸化来防止宿主细胞蛋白质合成的关闭。然而，无论细胞类型和状态如何，大多数细胞中缺失 ICP34.5 的 HSV 都不会诱导宿主细胞关闭。一般来说，分裂细胞支持缺失 ICP34.5 的 HSV 的复制；非分裂细胞则不能。此前作者表明 ICP34.5 与增殖细胞核抗原（PCNA）结合，PCNA 是细胞 DNA 复制和修复所必需的一种蛋白质。在此作者证明：（1）ICP34.5 与 PCNA 之间的相互作用涉及病毒蛋白的两个区域；（2）ICP34.5 与 HSV 复制蛋白形成一种具有 DNA 结合能力的复合物；（3）在感染早期，ICP34.5 在积聚于细胞质之前，与 PCNA 和 HSV 复制蛋白在细胞核中共定位；（4）ICP34.5 是一种病毒体蛋白。鉴于正在进行评估缺失 ICP34.5 的 HSV 的安全性和有效性的临床试验，了解 ICP34.5 在 HSV 复制中的作用至关重要。作者提出，在非分裂细胞中，需要 ICP34.5 将 PCNA 从修复模式转换为复制模式，这是启动 HSV 复制的先决条件。
