衣壳变构调节剂在干扰素给药期间增强乙型肝炎病毒感染肝

StephenW

衣壳变构调节剂在干扰素给药期间增强乙型肝炎病毒感染肝细胞的先天免疫反应

Keisuke Fukutomi 1 , Hayato Hikita 1 , Kazuhiro Murai 1 , Tasuku Nakabori 1 , Akiyoshi Shimoda 1 , Makoto Fukuoka 1 , Takuo Yamai 1 , Yuichiro Higuchi 2 , Kei Miyakawa 3 , Hiroshi Koide 3 , Akiyoshi Shimoda 1 1 , Ryotaro Sakamori 1 , Tomohide Tatsumi 1 , Tetsuo Takehara 1

隶属关系隶属关系

    1    日本大阪大阪大学医学研究生院胃肠病学和肝病学系。    2    日本川崎中央实验动物研究所实验动物研究部。    3    日本横滨市横滨市立大学医学院微生物学系。
    PMID：34558845 DOI：10.1002/hep4.1804

抽象的
衣壳变构调节剂 (CAM) 抑制乙型肝炎病毒 (HBV) 前基因组 RNA (pgRNA) 的衣壳化，其中包含与病原体相关的分子模式基序。然而，CAMs 对 HBV 感染肝细胞先天免疫反应的影响仍不清楚，我们在本研究中检查了这种影响。将 CAM 化合物 BAY41-4109 (BAY41) 施用于 HBV 感染的原代人肝细胞 (PHH) 不会改变总细胞质 p​​gRNA 水平，但显着降低衣壳内 pgRNA 水平，表明 BAY41 增加了细胞质中衣壳外 pgRNA 水平。 BAY41 单独没有改变细胞内干扰素 (IFN) 刺激的基因 (ISG) 表达水平。然而，BAY41 在 HBV 感染的 PHH 中增强了 IFN-α 对抗病毒 ISG 的诱导，但没有改变未感染 PHH 中 IFN-α 对 ISG 的诱导。与单独使用 BAY41 或 IFN-α 相比，BAY41 和 IFN-α 的共同给药显着抑制了细胞外 HBV-DNA 水平。 HBV 感染的人肝嵌合小鼠用载体、BAY41、聚乙二醇化 IFN-α (pegIFN-α) 或 BAY41 和 pegIFN-α 一起治疗。与载体对照相比，pegIFN-α 高度上调肝内 ISG 表达水平，但单独使用 BAY41 并未改变这些水平。 BAY41 和 pegIFN-α 的组合进一步增强了肝内抗病毒 ISG 表达，该表达被 pegIFNα 上调。 BAY41和pegIFN-α联合治疗的小鼠血清HBV-DNA水平在所有组中观察到的最低。
结论：当与外源性 IFN-α 结合时，CAM 增强了宿主 IFN 反应，这可能是由于细胞质外衣壳 pgRNA 的增加。© 2021 作者。由 Wiley Periodicals LLC 代表美国肝病研究协会出版的 Hepatology Communications。

StephenW

  Capsid Allosteric Modulators Enhance the Innate Immune Response in Hepatitis B Virus-Infected Hepatocytes During Interferon Administration
Keisuke Fukutomi  1 , Hayato Hikita  1 , Kazuhiro Murai  1 , Tasuku Nakabori  1 , Akiyoshi Shimoda  1 , Makoto Fukuoka  1 , Takuo Yamai  1 , Yuichiro Higuchi  2 , Kei Miyakawa  3 , Hiroshi Suemizu  2 , Akihide Ryo  3 , Ryoko Yamada  1 , Takahiro Kodama  1 , Ryotaro Sakamori  1 , Tomohide Tatsumi  1 , Tetsuo Takehara  1
Affiliations
Affiliations

    1
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
    2
    Laboratory Animal Research Department, Central Institute for Experimental Animals, Kawasaki, Japan.
    3
    Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.

    PMID: 34558845 DOI: 10.1002/hep4.1804

Abstract

Capsid allosteric modulators (CAMs) inhibit the encapsidation of hepatitis B virus (HBV) pregenomic RNA (pgRNA), which contains a pathogen-associated molecular pattern motif. However, the effect of CAMs on the innate immune response of HBV-infected hepatocytes remains unclear, and we examined this effect in this study. Administration of a CAM compound, BAY41-4109 (BAY41), to HBV-infected primary human hepatocytes (PHHs) did not change the total cytoplasmic pgRNA levels but significantly reduced intracapsid pgRNA levels, suggesting that BAY41 increased extracapsid pgRNA levels in the cytoplasm. BAY41 alone did not change the intracellular interferon (IFN)-stimulated gene (ISG) expression levels. However, BAY41 enhanced antiviral ISG induction by IFN-α in HBV-infected PHHs but did not change ISG induction by IFN-α in uninfected PHHs. Compared with BAY41 or IFN-α alone, coadministration of BAY41 and IFN-α significantly suppressed extracellular HBV-DNA levels. HBV-infected human liver-chimeric mice were treated with vehicle, BAY41, pegylated IFN-α (pegIFN-α), or BAY41 and pegIFN-α together. Compared with the vehicle control, pegIFN-α highly up-regulated intrahepatic ISG expression levels, but BAY41 alone did not change these levels. The combination of BAY41 and pegIFN-α further enhanced intrahepatic antiviral ISG expression, which was up-regulated by pegIFNα. The serum HBV-DNA levels in mice treated with the combination of BAY41 and pegIFN-α were the lowest observed in all the groups. Conclusion: CAMs enhance the host IFN response when combined with exogenous IFN-α, likely due to increased cytoplasmic extracapsid pgRNA.

© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

StephenW

https://aasldpubs.onlinelibrary. ... t/10.1002/hep4.1804