Duan Rui, de Vries Rory D, van Dun Jessica M, van Loenen Freek B, Osterhaus Albert D M E, Remeijer Lies, Verjans Georges M G M
Department of Virology, Erasmus Medical Centre, Rotterdam, the Netherlands.
J Infect Dis. 2009 Nov 1;200(9):1402-14. doi: 10.1086/606028.
The incidence and clinical significance of herpes simplex virus type 1 (HSV-1) acyclovir resistance were determined in patients with recurrent herpetic keratitis (RHK).
Sequential corneal isolates (n = 39) from 15 immunocompetent patients with RHK were assayed for acyclovir susceptibility and genotyped by analyzing the hypervariable regions of the HSV-1 genes US1 and US12. The thymidine kinase (TK) gene of each isolate was sequenced, and the proportion of acyclovir-resistant viruses within isolates was determined.
Uniform acyclovir-resistant or acyclovir-sensitive sequential isolates were identified in 4 and 2 patients, respectively. Notably, the acyclovir susceptibility of sequential isolates changed from acyclovir sensitive to acyclovir resistant (5 patients) or from acyclovir resistant to acyclovir sensitive (3 patients). The acyclovir-resistant phenotype of the isolates correlated with the patient's unresponsiveness to acyclovir therapy. Combined analyses of the TK gene and genotype of sequential isolates showed that acyclovir-sensitive isolates contained multiple acyclovir-resistant variants of the same virus and that an identical acyclovir-resistant HSV-1 strain reappeared in the patient's cornea during RHK episodes.
Corneal HSV-1 isolates are mixtures of acyclovir-sensitive and acyclovir-resistant viruses that share the same genotype but have different TK sequences. Recovery of the same acyclovir-resistant virus during consecutive herpetic keratitis episodes suggests that acyclovir-resistant HSV-1 establishes latency and reactivates intermittently to cause acyclovir-refractory RHK.
确定复发性疱疹性角膜炎（RHK）患者中1型单纯疱疹病毒（HSV-1）对阿昔洛韦耐药的发生率及其临床意义。
对15例免疫功能正常的RHK患者的连续角膜分离株（n = 39）进行阿昔洛韦敏感性检测，并通过分析HSV-1基因US1和US12的高变区进行基因分型。对每个分离株的胸苷激酶（TK）基因进行测序，并确定分离株中对阿昔洛韦耐药病毒的比例。
分别在4例和2例患者中鉴定出一致的对阿昔洛韦耐药或敏感的连续分离株。值得注意的是，连续分离株的阿昔洛韦敏感性从阿昔洛韦敏感变为阿昔洛韦耐药（5例患者）或从阿昔洛韦耐药变为阿昔洛韦敏感（3例患者）。分离株的阿昔洛韦耐药表型与患者对阿昔洛韦治疗无反应相关。对连续分离株的TK基因和基因型的联合分析表明，阿昔洛韦敏感分离株包含同一病毒的多个阿昔洛韦耐药变体，并且在RHK发作期间，同一阿昔洛韦耐药的HSV-1毒株在患者角膜中再次出现。
角膜HSV-1分离株是阿昔洛韦敏感和耐药病毒的混合物，它们具有相同的基因型但具有不同的TK序列。在连续的疱疹性角膜炎发作期间同一阿昔洛韦耐药病毒的复发表明，阿昔洛韦耐药的HSV-1建立潜伏状态并间歇性重新激活，导致对阿昔洛韦难治的RHK。
