Okuda Tomoko, Kurokawa Masahiko, Matsuo Koma, Honda Mariko, Niimura Michihito, Shiraki Kimiyasu
Department of Virology, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan.
J Med Virol. 2004 Jan;72(1):112-20. doi: 10.1002/jmv.10562.
The role of acyclovir-sensitive herpes simplex virus (HSV) was analyzed in the process of its replacement by a resistant virus in vitro and in vivo in the aspect of acyclovir therapy. The mode of replacement of acyclovir-sensitive HSV with acyclovir-resistant HSV was examined by the passages of acyclovir-sensitive wild type HSV in Vero cells under acyclovir-treatment. The development of resistance was monitored more adequately by counting the number of acyclovir-resistant viruses in 10,000 plaque forming units than by the conventional susceptibility assay. The resistance increased with the proportion of thymidine kinase-deficient (TK(-)) viruses, when the susceptibilities of acyclovir-treated HSV population to 5'-iodo-2'deoxyuridine and phosphonoacetic acid were examined. The increased resistance was due to the increased proportion of acyclovir-resistant virus but not intermediately resistant virus. Infection with mixtures of TK(-) and acyclovir-sensitive strains rendered TK(-) sensitive to acyclovir, and virus yields were reduced to the levels of acyclovir-sensitive virus in Vero cells. Their yield reduction depended on the proportion of acyclovir-sensitive viruses and induction of TK activity. This reduction in virus yields of the mixture of TK(-) and acyclovir-sensitive strains was confirmed by acyclovir treatment in the skin of mice with cutaneous infection. Acyclovir treatment combined with superinfection of acyclovir-sensitive virus delayed the development of herpetic skin lesions due to acyclovir-resistant virus and reduced virus yields in the infected skin. Acyclovir-sensitive virus plays an important role in suppressing the generation and replication of acyclovir-resistant virus during acyclovir therapy.
在阿昔洛韦治疗方面，分析了阿昔洛韦敏感型单纯疱疹病毒（HSV）在体外和体内被耐药病毒取代过程中的作用。通过在阿昔洛韦处理下，将阿昔洛韦敏感型野生型HSV在Vero细胞中传代，研究了阿昔洛韦敏感型HSV被阿昔洛韦耐药型HSV取代的模式。通过计算10000个空斑形成单位中阿昔洛韦耐药病毒的数量，比传统的药敏试验更能充分监测耐药性的发展。当检测阿昔洛韦处理的HSV群体对5'-碘-2'-脱氧尿苷和膦甲酸的敏感性时，耐药性随胸苷激酶缺陷（TK(-)）病毒比例的增加而增加。耐药性增加是由于阿昔洛韦耐药病毒比例增加，而非中度耐药病毒。用TK(-)和阿昔洛韦敏感株的混合物感染使TK(-)对阿昔洛韦敏感，并且在Vero细胞中病毒产量降低到阿昔洛韦敏感病毒的水平。它们的产量降低取决于阿昔洛韦敏感病毒的比例和TK活性的诱导。在皮肤感染的小鼠皮肤中进行阿昔洛韦处理，证实了TK(-)和阿昔洛韦敏感株混合物的病毒产量降低。阿昔洛韦处理与阿昔洛韦敏感病毒的重复感染相结合，延缓了由阿昔洛韦耐药病毒引起的疱疹性皮肤病变的发展，并降低了感染皮肤中的病毒产量。在阿昔洛韦治疗期间，阿昔洛韦敏感病毒在抑制阿昔洛韦耐药病毒的产生和复制中起重要作用。
