Pottage J C, Kessler H A
Department of Medicine, Rush Medical College, Chicago, Illinois, USA.
Infect Agents Dis. 1995 Sep;4(3):115-24.
Herpes simplex virus (HSV) infections are very common in the general population and can be treated with the nucleoside analogue acyclovir. Acyclovir is initially phosphorylated intracellularly in HSV-infected cells by a viral-specific thymidine kinase to acyclovir-monophosphate. The monophosphate is subsequently di- and triphosphorylated by host cellular kinases to the active form of the drug, which inhibits HSV DNA polymerase and incorporates into the elongating viral DNA and causes chain termination. Acyclovir resistance has been increasingly described and is caused by mutations in either the thymidine kinase or the DNA polymerase genes. These mutations result in decreased or absent HSV thymidine kinase production, altered affinity of the thymidine kinase for acyclovir-triphosphate, or altered affinity of the HSV DNA polymerase for acyclovir-triphosphate. Thymidine kinase deficiency accounts for approximately 95% of acyclovir-resistant isolates. Clinical disease due to acyclovir-resistant HSV occurs primarily in immunocompromised patients and is usually characterized by a chronic, progressive ulcerative mucocutaneous disease with prolonged shedding of virus. Several large surveys have been done in an effort to determine the incidence of in vitro and clinical acyclovir resistance. Among immunocompetent hosts, even those who have received > or = 6 years of continuous acyclovir, the prevalence of acyclovir-resistant isolates has remained stable at approximately 3%. Only three cases of clinical resistance of HSV to acyclovir have been reported. However, the incidence in immunocompromised patients, particularly those with AIDS and those who have had bone marrow transplants, is increasing. Transmission of acyclovir-resistant isolates from person to person has not been documented, but due to the increased use of acyclovir and newer drugs, such as famciclovir, there is great concern that this transmission might occur in the future. Continued surveillance in both immunocompetent and immunocompromised hosts for the development of clinical acyclovir-resistant HSV disease is necessary.
单纯疱疹病毒（HSV）感染在普通人群中非常常见，可用核苷类似物阿昔洛韦进行治疗。阿昔洛韦最初在HSV感染的细胞内通过病毒特异性胸苷激酶磷酸化成为单磷酸阿昔洛韦。随后，单磷酸阿昔洛韦被宿主细胞激酶进一步二磷酸化和三磷酸化，形成药物的活性形式，该活性形式可抑制HSV DNA聚合酶，并掺入延长的病毒DNA中导致链终止。阿昔洛韦耐药性的报道日益增多，其原因是胸苷激酶或DNA聚合酶基因发生突变。这些突变导致HSV胸苷激酶产生减少或缺失、胸苷激酶对三磷酸阿昔洛韦的亲和力改变，或HSV DNA聚合酶对三磷酸阿昔洛韦的亲和力改变。胸苷激酶缺乏约占阿昔洛韦耐药分离株的95%。由阿昔洛韦耐药HSV引起的临床疾病主要发生在免疫功能低下的患者中，通常表现为慢性、进行性溃疡性黏膜皮肤疾病，病毒持续排出。已经进行了几项大型调查，以确定体外和临床阿昔洛韦耐药性的发生率。在免疫功能正常的宿主中，即使是那些连续接受阿昔洛韦治疗≥6年的患者，阿昔洛韦耐药分离株的患病率仍稳定在约3%。仅报告了3例HSV对阿昔洛韦临床耐药的病例。然而，免疫功能低下患者，尤其是艾滋病患者和接受骨髓移植的患者中，阿昔洛韦耐药的发生率正在上升。虽然尚未有阿昔洛韦耐药分离株在人与人之间传播的记录，但由于阿昔洛韦和更昔洛韦等新药的使用增加，人们非常担心未来可能会发生这种传播。对免疫功能正常和免疫功能低下的宿主持续监测临床阿昔洛韦耐药HSV疾病的发生情况是必要的。
