Zarrouk Karima, Piret Jocelyne, Boivin Guy
Research Center in Infectious Diseases, CHU de Québec and Laval University, Quebec City, Quebec, Canada.
Research Center in Infectious Diseases, CHU de Québec and Laval University, Quebec City, Quebec, Canada.
Virus Res. 2017 Apr 15;234:177-192. doi: 10.1016/j.virusres.2017.01.019. Epub 2017 Jan 30.
Human herpesviruses are large double-stranded DNA viruses belonging to the Herpesviridae family. These viruses have the ability to establish lifelong latency into the host and to periodically reactivate. Primary infections and reactivations of herpesviruses cause a large spectrum of diseases and may lead to severe complications in immunocompromised patients. The viral DNA polymerase is a key enzyme in the lytic phase of the infection by herpesviruses. This review focuses on the structures and functions of viral DNA polymerases of herpes simplex virus (HSV) and human cytomegalovirus (HCMV). DNA polymerases of HSV (UL30) and HCMV (UL54) belong to B family DNA polymerases with which they share seven regions of homology numbered I to VII as well as a δ-region C which is homologous to DNA polymerases δ. These DNA polymerases are multi-functional enzymes exhibiting polymerase, 3'-5' exonuclease proofreading and ribonuclease H activities. Furthermore, UL30 and UL54 DNA polymerases form a complex with UL42 and UL44 processivity factors, respectively. The mechanisms involved in their polymerisation activity have been elucidated based on structural analyses of the DNA polymerase of bacteriophage RB69 crystallized under different conformations, i.e. the enzyme alone or in complex with DNA and with both DNA and incoming nucleotide. All antiviral agents currently used for the prevention or treatment of HSV and HCMV infections target the viral DNA polymerases. However, long-term administration of these antivirals may lead to the emergence of drug-resistant isolates harboring mutations in genes encoding viral enzymes that phosphorylate drugs (i.e., nucleoside analogues) and/or DNA polymerases.
人类疱疹病毒是属于疱疹病毒科的大型双链DNA病毒。这些病毒能够在宿主体内建立终身潜伏，并定期重新激活。疱疹病毒的原发性感染和重新激活会引发多种疾病，并可能在免疫功能低下的患者中导致严重并发症。病毒DNA聚合酶是疱疹病毒感染裂解阶段的关键酶。本综述重点关注单纯疱疹病毒（HSV）和人巨细胞病毒（HCMV）的病毒DNA聚合酶的结构和功能。HSV（UL30）和HCMV（UL54）的DNA聚合酶属于B家族DNA聚合酶，它们与B家族DNA聚合酶共有七个同源区域，编号为I至VII，以及一个与DNA聚合酶δ同源的δ区域C。这些DNA聚合酶是多功能酶，具有聚合酶、3'-5'核酸外切酶校对和核糖核酸酶H活性。此外，UL30和UL54 DNA聚合酶分别与UL42和UL44持续性因子形成复合物。基于对噬菌体RB69的DNA聚合酶在不同构象下（即单独的酶、与DNA结合以及与DNA和进入的核苷酸结合）结晶的结构分析，已经阐明了它们聚合活性所涉及的机制。目前用于预防或治疗HSV和HCMV感染的所有抗病毒药物都靶向病毒DNA聚合酶。然而，长期使用这些抗病毒药物可能会导致出现耐药菌株，这些菌株在编码磷酸化药物（即核苷类似物）的病毒酶和/或DNA聚合酶的基因中发生突变。
