McLaren C, Chen M S, Ghazzouli I, Saral R, Burns W H
Antimicrob Agents Chemother. 1985 Dec;28(6):740-4. doi: 10.1128/AAC.28.6.740.
A decrease in the in vitro sensitivity to acyclovir (ACV) was observed in successive isolates of herpes simplex virus type 1 from three immunocompromised patients during intravenous therapy with this drug. The ACV-resistant isolate from patient 1 was cross-resistant to dihydroxypropoxymethylguanine and bromovinyldeoxyuridine, but still susceptible to three fluoro-substituted pyrimidines, 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC), 2'-fluoro-5-iodo-1-beta-D-arabinofuranosyluracil (FIAU), and 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylthymine (FMAU). The thymidine kinase (TK) from the resistant isolate showed a 50-fold or greater reduction in affinity for thymidine, FIAU, FMAU, and ACV, but the total enzyme activity was similar to that of the sensitive isolate. The ACV-resistant isolate from patient 2 was also resistant to dihydroxypropoxymethylguanine, bromovinyldeoxyuridine, and the fluoro-substituted compounds; TK activity for this isolate was less than 1% of the patient's pretherapy isolate. An isolate obtained during a subsequent recurrence in patient 2 was susceptible to ACV and the other TK-dependent agents. The ACV-resistant isolate from patient 3 was partially resistant to FIAC and FIAU but still susceptible to FMAU; the viral TK had a 10-fold-lower affinity for ACV, FIAU, and FMAU than did the sensitive pretherapy isolate, while the level of TK activity detected was reduced to 6%. In none of the isolates studied was a change in sensitivity to phosphonoformic acid observed. Compared with the corresponding pretherapy ACV-sensitive isolates, there was a 30-fold decrease in neurovirulence for mice of the two drug-resistant isolates with diminished levels of thymidine-phosphorylating activity and no change in virulence for the third isolate. These findings indicate that mixed patterns of drug-resistance to TK-dependent antiviral compounds can occur in clinical isolates, resulting from changes in either the amount or the affinity of viral TK activity.
在三名免疫功能低下患者接受阿昔洛韦（ACV）静脉治疗期间，从其体内连续分离出的1型单纯疱疹病毒对ACV的体外敏感性出现下降。患者1的ACV耐药分离株对二羟基丙氧基甲基鸟嘌呤和溴乙烯基脱氧尿苷存在交叉耐药，但对三种含氟取代嘧啶，即2'-氟-5-碘-1-β-D-阿拉伯呋喃糖基胞嘧啶（FIAC）、2'-氟-5-碘-1-β-D-阿拉伯呋喃糖基尿嘧啶（FIAU）和2'-氟-5-碘-1-β-D-阿拉伯呋喃糖基胸腺嘧啶（FMAU）仍敏感。耐药分离株的胸苷激酶（TK）对胸苷、FIAU、FMAU和ACV的亲和力降低了50倍或更多，但总酶活性与敏感分离株相似。患者2的ACV耐药分离株对二羟基丙氧基甲基鸟嘌呤、溴乙烯基脱氧尿苷和含氟取代化合物也耐药；该分离株的TK活性不到患者治疗前分离株的1%。在患者2随后复发期间获得的一个分离株对ACV和其他依赖TK的药物敏感。患者3的ACV耐药分离株对FIAC和FIAU部分耐药，但对FMAU仍敏感；病毒TK对ACV、FIAU和FMAU的亲和力比治疗前敏感分离株低10倍，而检测到的TK活性水平降至6%。在所研究的分离株中，未观察到对膦甲酸的敏感性变化。与相应的治疗前ACV敏感分离株相比，两种胸苷磷酸化活性水平降低的耐药分离株对小鼠的神经毒力下降了30倍，而第三种分离株的毒力没有变化。这些发现表明，临床分离株中可能出现对依赖TK的抗病毒化合物的混合耐药模式，这是由病毒TK活性的量或亲和力变化导致的。
