Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity?
Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity?
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DOI：
10.7326/0003-4819-111-11-893
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发表时间：
1989-12
影响因子：
39.2
通讯作者：
Stephen L. Sacks;R. J. Wanklin;Donna E. Reece;Karen A. Hicks;Kenneth L. Tyler;Donald M. Coen
中科院分区：
文献类型：
--
作者：
Stephen L. Sacks;R. J. Wanklin;Donna E. Reece;Karen A. Hicks;Kenneth L. Tyler;Donald M. Coen
单纯疱疹临床获得性无环鸟苷耐药通常与病毒胸苷激酶缺乏有关，而这反过来又与动物模型中毒性减弱有关。胸苷激酶缺陷分离株致病性减弱是抗病毒耐药性临床意义争议的部分原因。我们报告了从一个患有严重进行性食管炎的病人身上分离出的一系列耐药病毒。这些分离物具有不同的胸苷激酶活性，与处理前获得的分离物的活性相比，从2.8%到130%不等；在脑炎模型中，耐药分离物615保留了酶活性和神经毒力。空斑纯化显示，一种异质混合物含有至少一种抗阿昔洛韦、抗磷膦的空斑分离物（615.8），完全能够磷酸化阿昔洛韦。从分离物615.8中纯化了含有大部分DNA聚合酶基因的3.3 kbp BamHI片段，并成功地转移了对阿昔洛韦和氟膦酸钠的抗性。体外获得无环鸟苷耐药性与临床疾病的进展、动物模型中致病性的维持以及病毒DNA聚合酶的至少一个突变有关。单纯疱疹感染患者在阿昔洛韦治疗期间出现进展，应在抗病毒化疗的背景下观察是否获得耐药性；未来的研究还应考虑这些患者中是否存在异质病毒群。
Clinically acquired acyclovir resistance in herpes simplex has usually been associated with a deficiency in viral thymidine kinase, which, in turn, has been linked with attenuated virulence in animal models. Diminished pathogenicity in thymidine kinase-deficient isolates has been partly responsible for controversies about the clinical significance of antiviral resistance. We report on a series of resistant virus isolates from a patient who had severe, progressive esophagitis. These isolates had various thymidine kinase activities, ranging from 2.8% to 130% when compared with the activity of the isolate obtained before treatment; the resistant isolate 615 retained enzyme activity as well as neurovirulence in an encephalitis model. Plaque purification showed a heterogeneous mixture containing at least one acyclovir-resistant, foscarnet-resistant plaque isolate (615.8) fully able to phosphorylate acyclovir. The 3.3-kbp BamHI fragment containing most of the DNA polymerase gene from isolate 615.8 was purified and used to successfully transfer both acyclovir and foscarnet resistance. Acquisition of in-vitro acyclovir resistance was associated with progression of clinical disease, as well as with maintenance of pathogenicity in an animal model and at least one mutation in viral DNA polymerase. Patients with herpes simplex infections that progress during acyclovir therapy should be observed for acquisition of resistance in the setting of antiviral chemotherapy; future studies should also consider the presence of heterogeneous virus populations in such patients.