Herpesviruses thymidine kinase (TK) and protein kinase (PK) allow the activation of nucleoside analogues used in anti-herpesvirus treatments. Mutations emerging in these two genes often lead to emergence of drug-resistant strains responsible for life-threatening diseases in immunocompromised populations. In this review, we analyze the binding of different nucleoside analogues to the TK active site of the three α-herpesviruses [Herpes Simplex Virus 1 and 2 (HSV-1 and HSV-2) and Varicella-Zoster Virus (VZV)] and present the impact of known mutations on the structure of the viral TKs. Furthermore, models of β-herpesviruses [Human cytomegalovirus (HCMV) and human herpesvirus-6 (HHV-6)] PKs allow to link amino acid changes with resistance to ganciclovir and/or maribavir, an investigational chemotherapeutic used in patients with multidrug-resistant HCMV. Finally, we set the basis for the understanding of drug-resistance in γ-herpesviruses [Epstein-Barr virus (EBV) and Kaposi’s sarcoma associated herpesvirus (KSHV)] TK and PK through the use of animal surrogate models.

疱疹病毒胸苷激酶（TK）和蛋白激酶（PK）可以激活抗疱疹病毒治疗中使用的核苷类似物。在这两个基因中出现的突变通常会导致导致免疫受损人群中威胁生命的疾病的耐药株的出现。在这篇综述中，我们分析了不同的核苷类似物与三种α-疱疹病毒[单纯疱疹病毒1和2（HSV-1和HSV-2）和水痘带状疱疹病毒（VZV）]的TK活性位点的结合已知突变对病毒TKs结构的影响。此外，β-疱疹病毒[人类巨细胞病毒（HCMV）和人类疱疹病毒6（HHV-6）] PK模型可将氨基酸变化与更昔洛韦和/或马立巴韦耐药性联系起来，这是一种对多药耐药性患者使用的研究性化疗药物HCMV。