Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.
J Virol. 2022 Sep 28;96(18):e0064622. doi: 10.1128/jvi.00646-22. Epub 2022 Aug 30.
Hepatitis A virus (HAV) infection is a major cause of acute viral hepatitis worldwide. Furthermore, HAV causes acute liver failure or acute-on-chronic liver failure. However, no potent anti-HAV drugs are currently available in the clinical situations. There have been some reports that amantadine, a broad-spectrum antiviral, suppresses HAV replication . Therefore, we examined the effects of amantadine and rimantadine, derivates of adamantane, on HAV replication, and investigated the mechanisms of these drugs. In the present study, we evaluated the effects of amantadine and rimantadine on HAV HM175 genotype IB subgenomic replicon replication and HAV HA11-1299 genotype IIIA replication in cell culture infection systems. Amantadine and rimantadine significantly inhibited HAV replication at the post-entry stage in Huh7 cells. HAV infection inhibited autophagy by suppressing the autophagy marker light chain 3 and reducing number of lysosomes. Proteomic analysis on HAV-infected Huh7 cells treated by amantadine and rimantadine revealed the changes of the expression levels in 42 of 373 immune response-related proteins. Amantadine and rimantadine inhibited HAV replication, partially through the enhancement of autophagy. Taken together, our results suggest a novel mechanism by which HAV replicates along with the inhibition of autophagy and that amantadine and rimantadine inhibit HAV replication by enhancing autophagy. Amantadine, a nonspecific antiviral medication, also effectively inhibits HAV replication. Autophagy is an important cellular mechanism in several virus-host cell interactions. The results of this study provide evidence indicating that autophagy is involved in HAV replication and plays a role in the HAV life cycle. In addition, amantadine and its derivative rimantadine suppress HAV replication partly by enhancing autophagy at the post-entry phase of HAV infection in human hepatocytes. Amantadine may be useful for the control of acute HAV infection by inhibiting cellular autophagy pathways during HAV infection processes.
甲型肝炎病毒（HAV）感染是全球急性病毒性肝炎的主要病因。此外，HAV 可导致急性肝衰竭或急性慢性肝衰竭。然而，在临床情况下，目前尚无有效的抗 HAV 药物。有一些报道称，金刚烷胺，一种广谱抗病毒药物，可抑制 HAV 复制。因此，我们研究了金刚烷胺和金刚乙胺（金刚烷的衍生物）对 HAV 复制的影响，并探讨了这些药物的作用机制。在本研究中，我们评估了金刚烷胺和金刚乙胺对 HAV HM175 基因型 IB 亚基因组复制子和 HAV HA11-1299 基因型 IIIA 在细胞培养感染系统中的复制的影响。金刚烷胺和金刚乙胺在 Huh7 细胞中明显抑制了 HAV 复制的进入后阶段。HAV 感染通过抑制自噬标志物 LC3 和减少溶酶体数量来抑制自噬。用金刚烷胺和金刚乙胺处理 HAV 感染的 Huh7 细胞的蛋白质组学分析显示，在 373 种免疫反应相关蛋白中有 42 种的表达水平发生了变化。金刚烷胺和金刚乙胺抑制 HAV 复制，部分是通过增强自噬。综上所述，我们的结果表明，HAV 通过抑制自噬来复制，而金刚烷胺和金刚乙胺通过增强自噬来抑制 HAV 复制，这是一种新的机制。金刚烷胺，一种非特异性抗病毒药物，也能有效抑制 HAV 复制。自噬是几种病毒-宿主细胞相互作用中的一种重要细胞机制。本研究的结果提供了证据表明，自噬参与 HAV 复制，并在 HAV 生命周期中发挥作用。此外，金刚烷胺及其衍生物金刚乙胺在 HAV 感染的人肝细胞中，通过在 HAV 感染的进入后阶段增强自噬，部分抑制 HAV 复制。金刚烷胺通过抑制 HAV 感染过程中的细胞自噬途径，可能对控制急性 HAV 感染有用。
