Genotypic Characterization of UL23 Thymidine Kinase and UL30 DNA Polymerase of Clinical Isolates of Herpes Simplex Virus: Natural Polymorphism and Mutations Associated with Resistance to Antivirals
Genotypic Characterization of UL23 Thymidine Kinase and UL30 DNA Polymerase of Clinical Isolates of Herpes Simplex Virus: Natural Polymorphism and Mutations Associated with Resistance to Antivirals
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DOI：
10.1128/aac.00669-10
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发表时间：
2010-11-01
影响因子：
4.9
通讯作者：
Boutolleau, David
中科院分区：
文献类型：
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作者：
Burrel, Sonia;Deback, Claire;Boutolleau, David
目前报道的单纯疱疹病毒（HSV）对干扰病毒DNA合成的抗病毒药物耐药的分子机制依赖于UL 23（胸苷激酶[TK]）和UL 30（DNA聚合酶）基因内存在的突变。基因型抗病毒耐药试验结果的解释需要明确区分耐药突变和天然菌株间序列变异。本工作的目的是广泛描述HSV-1和HSV-2毒株中UL 23 TK和UL 30 DNA聚合酶的天然多态性以及与HSV对抗病毒药物耐药潜在相关的氨基酸变化。进行全长UL 23和UL 30基因的序列分析。研究了94株药物敏感的临床分离株（43株HSV-1和51株HSV-2）和3株实验室菌株（科斯、gHSV-2和MS 2）的天然多态性，并分析了25株表现出抗病毒药物耐药表型特征的临床分离株的耐药突变。我们的研究结果表明，TK和DNA聚合酶是高度保守的HSV株，与HSV-2株的变异性较弱。本研究提供了HSV-1和HSV-2分离株中两种病毒酶天然多态性的精确图谱，分别鉴定了TK和DNA聚合酶先前从未描述过的15和51种多态性，这将有助于解释基因型抗病毒耐药试验。此外，25个耐药HSV分离株的基因型特征显示位于TK的8个新的氨基酸变化，并可能解释阿昔洛韦（ACV）耐药性。
The molecular mechanisms of herpes simplex virus (HSV) resistance to antiviral drugs interfering with viral DNA synthesis reported so far rely on the presence of mutations within UL23 (thymidine kinase [TK]) and UL30 (DNA polymerase) genes. The interpretation of genotypic antiviral resistance assay results requires the clear distinction between resistance mutations and natural interstrain sequence variations. The objectives of this work were to describe extensively the natural polymorphism of UL23 TK and UL30 DNA polymerase among HSV-1 and HSV-2 strains and the amino acid changes potentially associated with HSV resistance to antivirals. The sequence analysis of the full-length UL23 and UL30 genes was performed. Ninety-four drug-sensitive clinical isolates (43 HSV-1 and 51 HSV-2) and 3 laboratory strains (KOS, gHSV-2, and MS2) were studied for natural polymorphism, and 25 clinical isolates exhibiting phenotypic traits of resistance to antivirals were analyzed for drug resistance mutations. Our results showed that TK and DNA polymerase are highly conserved among HSV strains, with a weaker variability for HSV-2 strains. This study provided a precise map of the natural polymorphism of both viral enzymes among HSV-1 and HSV-2 isolates, with the identification of 15 and 51 polymorphisms never previously described for TK and DNA polymerase, respectively, which will facilitate the interpretation of genotypic antiviral-resistant testing. Moreover, the genotypic characterization of 25 drug-resistant HSV isolates revealed 8 new amino acid changes located in TK and potentially accounting for acyclovir (ACV) resistance.