Cyclopropavir Susceptibility of Cytomegalovirus DNA Polymerase Mutants Selected after Antiviral Drug Exposure
Cyclopropavir Susceptibility of Cytomegalovirus DNA Polymerase Mutants Selected after Antiviral Drug Exposure
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DOI：
10.1128/aac.05559-11
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发表时间：
2012-01-01
影响因子：
4.9
通讯作者：
Bowlin, Terry L.
中科院分区：
文献类型：
--
作者：
Chou, Sunwen;Marousek, Gail;Bowlin, Terry L.
采用标准化的基于产率降低的方法，检测了对目前抗病毒药物更昔洛韦（GCV）、膦甲酸（FOS）和西多福韦（CDV）具有已知耐药模式的人巨细胞病毒（CMV）UL 54 DNA聚合酶（pol）突变体对环丙帕韦（CPV）的敏感性。外切核酸酶和A987 G（V区）突变的密码子通常与双重GCV-CDV耐药的临床分离株矛盾地赋予增加CPV的易感性。各种聚合酶催化区突变赋予FOS抗性与可变的低级GCV和CDV交叉抗性也赋予CPV抗性，50%有效浓度（EC（50））增加3至13倍。加入UL 97突变株C592 G后，CPV对几种pol突变株的EC（50）值增加约2倍。CMV核酸外切酶突变体在CPV下的繁殖，所述CPV选择pol突变比UL 97突变更少。在21个实验中，检测到突变E756 D和M844 V各一个实例，其单独显示使CPV EC增加3至4倍（50）。与GCV和CDV不同，核酸外切酶突变不是CPV抗性的优选机制，但pol区III中和附近的突变可能通过影响其作为DNA聚合的传入碱基的识别而赋予CPV抗性。
Human cytomegalovirus (CMV) UL54 DNA polymerase (pol) mutants with known patterns of resistance to current antivirals ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV) were tested for cyclopropavir (CPV) susceptibility by a standardized reporter-based yield reduction assay. Exonuclease and A987G (region V) mutations at codons commonly associated with dual GCV-CDV resistance in clinical isolates paradoxically conferred increased CPV susceptibility. Various polymerase catalytic region mutations conferring FOS resistance with variable low-grade GCV and CDV cross-resistance also conferred CPV resistance, with 50% effective concentration (EC(50)) increases of 3- to 13-fold. CPV EC(50) values against several pol mutants were increased about 2-fold by adding UL97 mutation C592G. Propagation of a CMV exonuclease mutant under CPV selected for pol mutations less often than UL97 mutations. In 21 experiments, one instance each of mutations E756D and M844V, which were shown individually to confer 3- to 4-fold increases in CPV EC(50), was detected. Unlike GCV and CDV, exonuclease mutations are not a preferred mechanism of CPV resistance, but mutations in and near pol region III may confer CPV resistance by affecting its recognition as an incoming base for DNA polymerization.