Horsburgh B C, Chen S H, Hu A, Mulamba G B, Burns W H, Coen D M
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Infect Dis. 1998 Sep;178(3):618-25. doi: 10.1086/515375.
To investigate how acyclovir-resistant (ACVr) herpes simplex virus (HSV) evades drug therapy and causes disease, HSV-1 isolates from a bone marrow transplant (BMT) patient were studied. The patient developed ACVr disease after an initial BMT and, following a second BMT, reactivated ACVr HSV despite high-dose acyclovir prophylaxis. ACVr isolates from each episode contained the same point mutation in the viral thymidine kinase (tk) gene, documenting the emergence, latency, and reactivation of this mutant. The mutants were exceedingly impaired for TK activity in sensitive enzyme, plaque autoradiography, and drug-susceptibility assays. Nevertheless, these mutants and a tk deletion mutant constructed in the same genetic background reactivated from latency in mouse trigeminal ganglia, in contrast to similar mutants from laboratory strains. It is hypothesized that alleles in the clinical isolate compensate for the loss of TK in this animal model. Such genetic variability may be important for ACVr disease in humans.
为了研究耐阿昔洛韦（ACVr）的单纯疱疹病毒（HSV）如何逃避药物治疗并引发疾病，对一名骨髓移植（BMT）患者的HSV-1分离株进行了研究。该患者在首次BMT后患上了ACVr疾病，在第二次BMT后，尽管接受了高剂量阿昔洛韦预防，ACVr HSV仍被重新激活。每次发作的ACVr分离株在病毒胸苷激酶（tk）基因中都含有相同的点突变，证明了该突变体的出现、潜伏和重新激活。在敏感酶、噬斑放射自显影和药敏试验中，这些突变体的TK活性严重受损。然而，与实验室菌株的类似突变体不同，这些突变体和在相同遗传背景下构建的tk缺失突变体在小鼠三叉神经节中从潜伏状态重新激活。据推测，临床分离株中的等位基因在这种动物模型中补偿了TK的缺失。这种遗传变异性可能对人类的ACVr疾病很重要。
