Penciclovir and pathogenesis phenotypes of drug-resistant Herpes simplex virus mutants.
Penciclovir and pathogenesis phenotypes of drug-resistant Herpes simplex virus mutants.
复制标题
喷昔洛韦和耐药单纯疱疹病毒突变体的发病机制表型。
DOI：
10.1016/s0166-3542(97)00054-5
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发表时间：
1998
影响因子：
7.6
通讯作者：
Coen,DM
中科院分区：
文献类型：
--
作者：
Pelosi,E;Mulamba,GB;Coen,DM
我们比较了对无环鸟苷和/或氟膦酸钠耐药的单纯疱疹病毒1型突变体对喷昔洛韦的敏感性和发病表型。这些突变体来源于实验室菌株KOS，包括6个DNA聚合酶突变体、1个胸苷激酶阴性突变体、1个胸苷激酶部分突变体和1个双突变体。先前未检测喷昔洛韦敏感性的四种聚合酶突变体中有两种对该药物表现出适度的耐药性。胸苷激酶阴性突变体表现出约20倍的耐药性，而胸苷激酶部分突变体对喷昔洛韦敏感。在7周龄CD1小鼠脑内接种后，突变体表现出接近野生型的神经毒力（胸苷激酶部分），适度衰减（例如胸苷激酶阴性）到更严重的衰减。在角膜接种后，三种聚合酶突变体表现出适度的缺陷（相对于胸苷激酶阴性突变体），它们在神经节中急性复制和从潜伏期重新激活的能力。对于突变体AraAr13，通过对标记拯救衍生的重组病毒的分析表明，神经节复制的缺陷是由于其聚合酶突变引起的。这些结果可能对喷昔洛韦的作用和耐药性、临床耐药性以及疱疹病毒与外周和中枢神经系统的相互作用等问题产生影响。
We compared the penciclovir susceptibilities and pathogenesis phenotypes of mutants of Herpes simplex virus type 1 that are resistant to acyclovir and/or foscarnet. The mutants, which were derived from laboratory strain KOS, included six DNA polymerase mutants, a thymidine kinase negative mutant, a thymidine kinase partial mutant, and a double mutant. Two of four polymerase mutants not previously examined for penciclovir susceptibility exhibited modest resistance to this drug. A thymidine kinase negative mutant exhibited ∼20-fold resistance while a thymidine kinase partial mutant was penciclovir-sensitive. Following intracerebral inoculation of 7-week old CD1 mice, the mutants ranged from exhibiting near wild-type neurovirulence (thymidine kinase partial) to modest attenuation (e.g. thymidine kinase negative) to more severe attenuation. Following corneal inoculation, three polymerase mutants exhibited modest deficits (relative to those of thymidine kinase negative mutants) in their abilities to replicate acutely in the ganglion and reactivate from latency. For mutant AraAr13, the deficit in ganglionic replication was shown to be due to its polymerase mutation by analysis of recombinant viruses derived by marker rescue. These results may have implications for issues of penciclovir action and resistance, for drug resistance in the clinic, and for the interactions of herpes viruses with the peripheral and central nervous systems.