Pelosi E, Mulamba G B, Coen D M
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Antiviral Res. 1998 Jan;37(1):17-28. doi: 10.1016/s0166-3542(97)00054-5.
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 approximately 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 AraA(r)13, 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.
我们比较了单纯疱疹病毒1型对阿昔洛韦和/或膦甲酸钠耐药的突变体的喷昔洛韦敏感性和致病表型。这些突变体源自实验室菌株KOS，包括六个DNA聚合酶突变体、一个胸苷激酶阴性突变体、一个胸苷激酶部分突变体和一个双突变体。四个之前未检测喷昔洛韦敏感性的聚合酶突变体中有两个对该药物表现出适度耐药。一个胸苷激酶阴性突变体表现出约20倍的耐药性，而一个胸苷激酶部分突变体对喷昔洛韦敏感。在对7周龄的CD1小鼠进行脑内接种后，这些突变体的神经毒力从接近野生型（胸苷激酶部分突变体）到适度减弱（如胸苷激酶阴性突变体）再到更严重的减弱。角膜接种后，三个聚合酶突变体在神经节中急性复制和从潜伏状态重新激活的能力方面表现出适度缺陷（相对于胸苷激酶阴性突变体）。对于突变体AraA(r)13，通过对标记拯救衍生的重组病毒的分析表明，神经节复制缺陷是由于其聚合酶突变。这些结果可能对喷昔洛韦的作用和耐药性问题、临床中的耐药性以及疱疹病毒与外周和中枢神经系统的相互作用具有重要意义。
