Division of Infectious Diseases, Oregon Health and Science University and Department of Veterans Affairs Medical Center, Portland, OR, USA.
Antiviral Res. 2021 Nov;195:105181. doi: 10.1016/j.antiviral.2021.105181. Epub 2021 Sep 21.
Acyclovir has weak activity against human cytomegalovirus (CMV). Despite some efficacy as prophylaxis, more potent anti-CMV drugs are preferred. Acyclovir resistance of CMV has been little studied. The viral UL97 kinase phosphorylates acyclovir, and cross-resistance of ganciclovir-resistant mutants is documented. However, UL54 exonuclease domain mutants may confer ganciclovir and cidofovir resistance by a mechanism that does not apply to acyclovir as an obligate chain terminator. To test for differential susceptibilities, 11 exonuclease domain mutants were tested for their 50% inhibitory concentrations (EC50s) of acyclovir in comparison with cidofovir. The 5 mutants with the highest cidofovir EC50s (>10-fold increased over wild type) all had acyclovir EC50s less than 20% of wild type. The relatively common N408K mutant had an acyclovir EC50 of 6 μM, comparable to that reported for wild type varicella-zoster virus. Several foscarnet-resistant UL54 mutants outside the exonuclease domains, some with low-grade ganciclovir/cidofovir cross-resistance, showed various degrees of acyclovir resistance. Based on these in vitro data, acyclovir may become a therapeutic option when a highly cidofovir-resistant exonuclease mutation is present without a simultaneous mutation in UL97.
阿昔洛韦对人类巨细胞病毒 (CMV) 的活性较弱。尽管作为预防药物有一定疗效，但更有效的抗 CMV 药物更受欢迎。CMV 对阿昔洛韦的耐药性研究甚少。病毒 UL97 激酶使阿昔洛韦磷酸化，并且已经记录了更昔洛韦耐药突变体的交叉耐药性。然而，UL54 外切酶结构域突变体可能通过一种不适用于阿昔洛韦作为强制性链终止剂的机制赋予更昔洛韦和西多福韦耐药性。为了测试差异敏感性，将 11 个外切酶结构域突变体与西多福韦进行比较，测试它们对阿昔洛韦的 50%抑制浓度 (EC50)。与野生型相比，具有最高西多福韦 EC50 值（增加 10 倍以上）的 5 个突变体的阿昔洛韦 EC50 值均小于野生型的 20%。相对常见的 N408K 突变体的阿昔洛韦 EC50 为 6μM，与报道的野生型水痘带状疱疹病毒相当。外切酶结构域外的几种膦甲酸耐药 UL54 突变体，有些具有低度更昔洛韦/西多福韦交叉耐药性，表现出不同程度的阿昔洛韦耐药性。根据这些体外数据，当存在高度西多福韦耐药的外切酶突变而 UL97 同时没有突变时，阿昔洛韦可能成为一种治疗选择。
