Kristofferson A, Ericson A C, Sohl-Akerlund A, Datema R
Department of Antiviral Therapy, Astra Alab AB, Södertälje, Sweden.
J Gen Virol. 1988 Jun;69 ( Pt 6):1157-66. doi: 10.1099/0022-1317-69-6-1157.
The herpesvirus DNA polymerase inhibitor foscarnet, applied topically, and the anti-herpesvirus guanosine analogue buciclovir, given orally, decreased virus replication and disease development in primary skin infections of mice caused by herpes simplex virus type 1 (HSV-1). If the same tissues were infected via sensory nerves, following zosteriform spread of the virus the same treatments showed strongly decreased efficacy, or were inefficacious, when started before development of clinical signs in the infected tissues. These results were obtained in murine models of zosteriform spread of HSV-1 to the ear (following inoculation of the ventral side of the neck) or to the lower flank (following inoculation of the upper flank). In these models the immune system played a dominant role in virus clearance. The topically applied foscarnet could not prevent disease development in these models of recrudescent disease even when applied before the virus was detected in the skin, but a decrease in virus titre was obtained. Orally administered buciclovir lost efficacy when administered at the time of virus entry into the skin, i.e. 1 or 2 days before development of clinical signs. In the flank model, measuring lesion development, orally administered acyclovir also had a strongly decreased efficacy, when compared with its effect during infections in which lesion development did not involve translocation of virus through nerves. In the presence of developing immunity the inhibitors could not accelerate the clearance of virus from infected tissues. Furthermore, all treatments (topical foscarnet and oral buciclovir or acyclovir) were without effect on disease development when treatment was initiated on appearance of the first clinical signs of disease. As disease development following zosteriform spread of HSV resembles that in recurrent herpes in humans, and as the limited efficacy of the inhibitors observed resembles the poor results obtained with inhibitors of herpesvirus DNA synthesis in clinical studies on the treatment of symptomatic recurrent herpes, we suggest the use of animal models of zosteriform spread for pre-clinical evaluation of new antiherpes drugs.
局部应用的疱疹病毒DNA聚合酶抑制剂膦甲酸钠和口服的抗疱疹病毒鸟苷类似物布昔洛韦，可减少1型单纯疱疹病毒（HSV-1）引起的小鼠原发性皮肤感染中的病毒复制和疾病发展。如果相同组织通过感觉神经感染，在病毒沿带状疱疹样扩散后，当在受感染组织出现临床体征之前开始相同治疗时，疗效会大幅降低或无效。这些结果是在HSV-1向耳部（接种颈部腹侧后）或下侧腹（接种上侧腹后）带状疱疹样扩散的小鼠模型中获得的。在这些模型中，免疫系统在病毒清除中起主导作用。局部应用的膦甲酸钠即使在皮肤中检测到病毒之前应用，也无法预防这些复发性疾病模型中的疾病发展，但可使病毒滴度降低。口服布昔洛韦在病毒进入皮肤时（即临床体征出现前1或2天）给药时失去疗效。在侧腹模型中，测量病变发展情况，与在病变发展不涉及病毒通过神经转移的感染期间相比，口服阿昔洛韦的疗效也大幅降低。在免疫力发展的情况下，抑制剂无法加速病毒从受感染组织中的清除。此外，当在疾病的首个临床体征出现时开始治疗，所有治疗（局部膦甲酸钠和口服布昔洛韦或阿昔洛韦）对疾病发展均无影响。由于HSV带状疱疹样扩散后的疾病发展与人类复发性疱疹相似，且观察到的抑制剂有限疗效类似于疱疹病毒DNA合成抑制剂在有症状复发性疱疹治疗临床研究中获得的不佳结果，我们建议使用带状疱疹样扩散的动物模型对新的抗疱疹药物进行临床前评估。
