In Vitro-Selected Drug-Resistant Varicella-Zoster Virus Mutants in the Thymidine Kinase and DNA Polymerase Genes Yield Novel Phenotype-Genotype Associations and Highlight Differences between Antiherpesvirus Drugs
In Vitro-Selected Drug-Resistant Varicella-Zoster Virus Mutants in the Thymidine Kinase and DNA Polymerase Genes Yield Novel Phenotype-Genotype Associations and Highlight Differences between Antiherpesvirus Drugs
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DOI：
10.1128/jvi.06620-11
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发表时间：
2012-03-01
影响因子：
5.4
通讯作者：
Snoeck, R.
中科院分区：
文献类型：
--
作者：
Andrei, G.;Topalis, D.;Snoeck, R.
水痘带状疱疹病毒（VZV）通常与免疫功能正常的患者的轻中度疾病有关。然而，年龄较大和免疫缺陷是与病毒再激活和严重并发症相关的最重要风险因素。VZV感染的治疗基于核苷类似物，如阿昔洛韦（ACV）及其戊基前药valacyclovir，喷昔洛韦（PCV）作为其前药famciclovir，以及在某些地区使用的bromovinyldeoxyuridine （BVDU; brivudin）。焦磷酸盐类似物foscarnet （PFA）的使用仅限于抗ACV(ACV(r)) VZV感染。由于抗病毒药物耐药性是一个新出现的问题，我们试图描述在ACV， BVDU及其衍生物BVaraU（索利夫定）和双环嘧啶核苷类似物（BCNAs）选择后发现的病毒胸苷激酶（TK）基因特异性突变的贡献，BVDU和BVaraU（索利夫定）是一类新的有效和特异性抗vzv药物。VZV TK基因493 ~ 498核苷酸上的6个Cs似乎是核苷酸插入或缺失的热点。VZV TK中新的氨基酸取代（G24R和T86A）也与耐药有关。在对PFA、PCV和2-phophonylmethoxyethyl （PME）嘌呤衍生物产生抗性的病毒中，在VZV DNA聚合酶的“掌区”发现了6个突变。对VZV TK或DNA聚合酶特异性突变对抗病毒药物耐药的贡献及其对病毒蛋白结构的影响的研究表明了交叉耐药的特定模式，并突出了ACV和PCV之间的重要差异，不仅在不同类别的抗病毒药物之间，而且在ACV和PCV之间。
Varicella zoster virus (VZV) is usually associated with mild to moderate illness in immunocompetent patients. However, older age and immune deficiency are the most important risk factors linked with virus reactivation and severe complications. Treatment of VZV infections is based on nucleoside analogues, such as acyclovir (ACV) and its valyl prodrug valacyclovir, penciclovir (PCV) as its prodrug famciclovir, and bromovinyldeoxyuridine (BVDU; brivudin) in some areas. The use of the pyrophosphate analogue foscarnet (PFA) is restricted to ACV-resistant (ACV(r)) VZV infections. Since antiviral drug resistance is an emerging problem, we attempt to describe the contributions of specific mutations in the viral thymidine kinase (TK) gene identified following selection with ACV, BVDU and its derivative BVaraU (sorivudine), and the bicyclic pyrimidine nucleoside analogues (BCNAs), a new class of potent and specific anti-VZV agents. The string of 6 Cs at nucleotides 493 to 498 of the VZV TK gene appeared to function as a hot spot for nucleotide insertions or deletions. Novel amino acid substitutions (G24R and T86A) in VZV TK were also linked to drug resistance. Six mutations were identified in the "palm domain" of VZV DNA polymerase in viruses selected for resistance to PFA, PCV, and the 2-phophonylmethoxyethyl (PME) purine derivatives. The investigation of the contributions of specific mutations in VZV TK or DNA polymerase to antiviral drug resistance and their impacts on the structures of the viral proteins indicated specific patterns of cross-resistance and highlighted important differences, not only between distinct classes of antivirals, but also between ACV and PCV.