Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA.
J Virol. 2018 Sep 26;92(20). doi: 10.1128/JVI.00994-18. Print 2018 Oct 15.
Alphaherpesvirus-associated ocular infections in humans caused by human alphaherpesvirus 1 (HHV-1) remain challenging to treat due to the frequency of drug application required and the potential for the selection of drug-resistant viruses. Repurposing on-the-market drugs is a viable strategy to accelerate the pace of drug development. It has been reported that the human immunodeficiency virus (HIV) integrase inhibitor raltegravir inhibits HHV-1 replication by targeting the DNA polymerase accessory factor and limits terminase-mediated genome cleavage of human betaherpesvirus 5 (HHV-5). We have previously shown, both and , that raltegravir can also inhibit the replication of felid alphaherpesvirus 1 (FeHV-1), a common ocular pathogen of cats with a pathogenesis similar to that of HHV-1 ocular disease. In contrast to what was reported for HHV-1, we were unable to select for a raltegravir-resistant FeHV-1 strain in order to define any basis for drug action. A candidate-based approach to explore the mode of action of raltegravir against FeHV-1 showed that raltegravir did not impact FeHV-1 terminase function, as described for HHV-5. Instead, raltegravir inhibited DNA replication, similarly to HHV-1, but by targeting the initiation of viral DNA replication rather than elongation. In addition, we found that raltegravir specifically repressed late gene expression independently of DNA replication, and both activities are consistent with inhibition of ICP8. Taken together, these results suggest that raltegravir could be a valuable therapeutic agent against herpesviruses. The rise of drug-resistant herpesviruses is a longstanding concern, particularly among immunocompromised patients. Therefore, therapies targeting viral proteins other than the DNA polymerase that may be less likely to lead to drug-resistant viruses are urgently needed. Using FeHV-1, an alphaherpesvirus closely related to HHV-1 that similarly causes ocular herpes in its natural host, we found that the HIV integrase inhibitor raltegravir targets different stages of the virus life cycle beyond DNA replication and that it does so without developing drug resistance under the conditions tested. This shows that the drug could provide a viable strategy for the treatment of herpesvirus infections.
人疱疹病毒 1（HHV-1）引起的人α疱疹病毒相关眼部感染由于需要频繁用药以及可能选择耐药病毒，因此仍然难以治疗。重新利用市售药物是加速药物开发的可行策略。据报道，人类免疫缺陷病毒（HIV）整合酶抑制剂拉替拉韦通过靶向 DNA 聚合酶辅助因子抑制 HHV-1 复制，并限制人疱疹病毒 5（HHV-5）的末端酶介导的基因组切割。我们之前已经表明，拉替拉韦既可以抑制猫常见眼部病原体猫疱疹病毒 1（FeHV-1）的复制，也可以抑制猫疱疹病毒 1（FeHV-1）的复制，其发病机制与 HHV-1 眼部疾病相似。与报道的 HHV-1 不同，我们无法选择拉替拉韦耐药的 FeHV-1 株，以确定任何药物作用的基础。基于候选药物的方法探索拉替拉韦对 FeHV-1 的作用机制表明，拉替拉韦不影响 FeHV-1 末端酶功能，如 HHV-5 所述。相反，拉替拉韦抑制 DNA 复制，与 HHV-1 相似，但靶向病毒 DNA 复制的起始而不是延伸。此外，我们发现拉替拉韦特异性地抑制 DNA 复制独立的晚期基因表达，并且这两种活性都与抑制 ICP8 一致。总之，这些结果表明拉替拉韦可能是治疗疱疹病毒的有价值的药物。耐药疱疹病毒的出现是一个长期存在的问题，特别是在免疫功能低下的患者中。因此，迫切需要针对 DNA 聚合酶以外的病毒蛋白的治疗方法，这些方法可能不太可能导致耐药病毒。使用 FeHV-1，一种与 HHV-1 密切相关的α疱疹病毒，在其自然宿主中同样引起眼部疱疹，我们发现 HIV 整合酶抑制剂拉替拉韦针对病毒生命周期的不同阶段，除了 DNA 复制之外，并且在测试条件下不会产生耐药性。这表明该药物可以为治疗疱疹病毒感染提供可行的策略。
