Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
J Virol. 2020 Aug 31;94(18). doi: 10.1128/JVI.00710-20.
Human adenoviruses (HAdV) are ubiquitous within the human population and comprise a significant burden of respiratory illnesses worldwide. Pediatric and immunocompromised individuals are at particular risk for developing severe disease; however, no approved antiviral therapies specific to HAdV exist. Ivermectin is an FDA-approved broad-spectrum antiparasitic drug that also exhibits antiviral properties against a diverse range of viruses. Its proposed function is inhibiting the classical protein nuclear import pathway mediated by importin-α (Imp-α) and -β1 (Imp-β1). Many viruses, including HAdV, rely on this host pathway for transport of viral proteins across the nuclear envelope. In this study, we show that ivermectin inhibits HAdV-C5 early gene transcription, early and late protein expression, genome replication, and production of infectious viral progeny. Similarly, ivermectin inhibits genome replication of HAdV-B3, a clinically important pathogen responsible for numerous recent outbreaks. Mechanistically, we show that ivermectin disrupts binding of the viral E1A protein to Imp-α without affecting the interaction between Imp-α and Imp-β1. Our results further extend ivermectin's broad antiviral activity and provide a mechanistic underpinning for its mode of action as an inhibitor of cellular Imp-α/β1-mediated nuclear import. Human adenoviruses (HAdVs) represent a ubiquitous and clinically important pathogen without an effective antiviral treatment. HAdV infections typically cause mild symptoms; however, individuals such as children, those with underlying conditions, and those with compromised immune systems can develop severe disseminated disease. Our results demonstrate that ivermectin, an FDA-approved antiparasitic agent, is effective at inhibiting replication of several HAdV types This is in agreement with the growing body of literature suggesting ivermectin has broad antiviral activity. This study expands our mechanistic knowledge of ivermectin by showing that ivermectin targets the ability of importin-α (Imp-α) to recognize nuclear localization sequences, without effecting the Imp-α/β1 interaction. These data also exemplify the applicability of targeting host factors upon which viruses rely as a viable antiviral strategy.
人类腺病毒（HAdV）在人类中普遍存在，是全球呼吸道疾病的重要负担。儿科和免疫功能低下的个体尤其有患严重疾病的风险；然而，目前尚无针对 HAdV 的批准的抗病毒疗法。伊维菌素是一种获得 FDA 批准的广谱抗寄生虫药物，对多种病毒也具有抗病毒特性。其作用机制是抑制由 Importin-α（Imp-α）和 Importin-β1（Imp-β1）介导的经典蛋白核输入途径。许多病毒，包括 HAdV，都依赖于这种宿主途径来将病毒蛋白运输穿过核膜。在这项研究中，我们表明伊维菌素抑制 HAdV-C5 早期基因转录、早期和晚期蛋白表达、基因组复制和感染性病毒颗粒的产生。同样，伊维菌素抑制 HAdV-B3 的基因组复制，HAdV-B3 是一种重要的临床病原体，导致了最近许多暴发。机制上，我们表明伊维菌素破坏了病毒 E1A 蛋白与 Imp-α 的结合，而不影响 Imp-α 与 Imp-β1 的相互作用。我们的结果进一步扩展了伊维菌素的广泛抗病毒活性，并为其作为细胞 Imp-α/β1 介导的核输入抑制剂的作用机制提供了依据。
人类腺病毒（HAdVs）是一种普遍存在且具有重要临床意义的病原体，目前尚无有效的抗病毒治疗方法。HAdV 感染通常会引起轻微症状；然而，儿童、有基础疾病的人以及免疫系统受损的人可能会发展为严重的全身性疾病。我们的结果表明，伊维菌素，一种获得 FDA 批准的抗寄生虫药物，能有效抑制几种 HAdV 类型的复制。这与越来越多的文献一致，表明伊维菌素具有广泛的抗病毒活性。这项研究通过表明伊维菌素靶向 Importin-α（Imp-α）识别核定位序列的能力，而不影响 Imp-α/β1 相互作用，扩展了我们对伊维菌素作用机制的认识。这些数据还说明了针对病毒依赖的宿主因子作为可行的抗病毒策略的适用性。
