Omura Natsumi, Fujii Hikaru, Yoshikawa Tomoki, Yamada Souichi, Harada Shizuko, Inagaki Takuya, Shibamura Miho, Takeyama Haruko, Saijo Masayuki
Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo, Japan.
Virol J. 2017 Mar 21;14(1):59. doi: 10.1186/s12985-017-0728-2.
Acyclovir (ACV)-resistant (ACVr) herpes simplex virus type 1 (HSV-1) infections are concern in immunocompromised patients. Most clinical ACVr HSV-1 isolates have mutations in the viral thymidine kinase (vTK) genes. The vTK-associated ACVr HSV-1 shows reduced virulence, but the association between the level of resistance and the virulence of the vTK-associated ACVr HSV-1 is still unclear.
The virulence in mice of 5 vTK-associated ACVr HSV-1 clones with a variety of ACV sensitivities, when inoculated through intracerebral and corneal routes, was evaluated in comparison with ACV-sensitive (ACVs) parent HSV-1 TAS.
Although all the 5 ACVr HSV-1 clones and ACVs HSV-1 TAS showed a similar single-step growth capacity in vitro, the virulence of ACVr HSV-1 clones significantly decreased. A 50% lethal dose (LD) of each clone was closely correlated with 50% inhibitory concentrations (IC), demonstrating that the higher the ACV-sensitvity, the the higher the virulence among the ACVr clones. One of the ACVr HSV-1 clones with a relatively low IC value maintained similar virulence to that of the parent TAS. The infection in mice with ACVr HSV-1 due to a single amino acid substitution in vTK induced local diseases, keratitis and dermatitis, while vTK-deficient clone did not.
A statistically significant correlation between the virulence and susceptibility to ACV among ACVr HSV-1 clones was demonstrated.
耐阿昔洛韦（ACV）的1型单纯疱疹病毒（HSV-1）感染是免疫功能低下患者所关注的问题。大多数临床耐ACV的HSV-1分离株在病毒胸苷激酶（vTK）基因中存在突变。与vTK相关的耐ACV的HSV-1毒力降低，但vTK相关的耐ACV的HSV-1的耐药水平与毒力之间的关联仍不清楚。
通过脑内和角膜途径接种，评估5个对ACV具有不同敏感性的与vTK相关的耐ACV的HSV-1克隆株相对于ACV敏感（ACVs）的亲本HSV-1 TAS在小鼠中的毒力。
尽管所有5个耐ACV的HSV-1克隆株和ACVs HSV-1 TAS在体外均表现出相似的单步生长能力，但耐ACV的HSV-1克隆株的毒力显著降低。每个克隆株的50%致死剂量（LD）与50%抑制浓度（IC）密切相关，表明在耐ACV的克隆株中，ACV敏感性越高，毒力越高。其中一个IC值相对较低的耐ACV的HSV-1克隆株与亲本TAS的毒力相似。vTK中单个氨基酸取代导致的耐ACV的HSV-1感染小鼠会引发局部疾病、角膜炎和皮炎，而vTK缺陷克隆株则不会。
耐ACV的HSV-1克隆株的毒力与对ACV的敏感性之间存在统计学上的显著相关性。
