Field H J, Darby G
Antimicrob Agents Chemother. 1980 Feb;17(2):209-16. doi: 10.1128/AAC.17.2.209.
Mice infected with three different isolates of herpes simplex virus (HSV) and treated with acyclovir (acycloguanosine; ACV) showed low levels of virus replication during the acute phase of infection. However, virus isolated from such treated mice did not show increased resistance to ACV. In contrast, resistant virus was readily isolated in vitro by passaging HSV in the presence of the drug. The degree of resistance was determined, in part, by the nature of the cells used to test the virus. The majority of ACV-resistant strains induced low or undetectable levels of HSV-specified thymidine kinase (TK), the enzyme responsible for phosphorylating ACV in infected cells. The TK-resistant strains were attenuated when injected into mice as indicated by reductions in virus replication, inflammation, and establishment of latent infections in sensory ganglia. The reduced virulence of the TK- strains was most marked after intracerebral inoculation, where the lethal dose was increased more than 100-fold compared with the parental isolates. However, one mutant is described which induced high levels of TK but was highly resistant to ACV and retained virulence for mice.
感染三种不同单纯疱疹病毒（HSV）分离株并接受阿昔洛韦（无环鸟苷；ACV）治疗的小鼠在感染急性期病毒复制水平较低。然而，从这些接受治疗的小鼠中分离出的病毒对ACV并未表现出更高的抗性。相比之下，通过在药物存在的情况下传代HSV，可在体外轻松分离出抗性病毒。抗性程度部分取决于用于检测病毒的细胞性质。大多数对ACV耐药的毒株诱导产生低水平或无法检测到的HSV特异性胸苷激酶（TK），该酶负责在受感染细胞中磷酸化ACV。当将TK抗性毒株注射到小鼠体内时，如病毒复制、炎症反应以及感觉神经节中潜伏感染的建立减少所示，其毒力减弱。TK - 毒株的毒力降低在脑内接种后最为明显，与亲本分离株相比，其致死剂量增加了100多倍。然而，描述了一种突变体，其诱导产生高水平的TK，但对ACV高度耐药且对小鼠仍具有毒力。
