Hepatitis C virus infection suppresses hepatitis B virus replication via the RIG-I-like helicase pathway

Kazuhiro Murai,Ryo Fukuda,Tetsuo Takehara,Yasuteru Kondo,Akihide Ryo,Hayato Hikita,Ryotaro Sakamori,Yugo Kai,Takahiro Kodama,Tomohide Tatsumi,Ryoko Yamada,Tasuku Nakabori,Kei Miyakawa,Takeshi Takahashi,Makoto Fukuoka,Keisuke Fukutomi,Takuo Yamai,Hiroshi Suemizu,Akira Doi

doi:10.1038/s41598-020-57603-9

Abstract

Mechanisms of hepatitis B virus (HBV) reactivation after hepatitis C virus (HCV) elimination by direct-acting antiviral (DAA) treatment in HBV/HCV-co-infected patients remain unclear. We examined RIG-I-like helicase (RLH) pathway activation by HBV mono-infection, HCV mono-infection or HBV/HCV co-infection and interference between HBV and HCV in primary human hepatocytes. Interference between HBV and HCV and HBV reactivation after DAA treatment in humanized-liver mice were assessed. HCV infection activated RLH pathway, as evidenced by RIG-I, ISG15 and ISG56 expression induction; HBV caused only RIG-I induction in vitro. RLH activation was also found in HBV/HCV-co-infected cells, and HBV replication were suppressed in HBV/HCV-co-infected than in HBV-mono-infected cells. siRNA-mediated double knockdown of ISG15 and ISG56 increased HBV replication in HBV/HCV-co-infected cells. HCV infection activated RLH pathway and suppressed HBV replication in humanized-liver mice. Subsequent elimination of HCV by DAA administration downregulated RLH pathway and upregulated HBV replication in mice. RLH pathway was activated in livers of chronic hepatitis C patients compared to those of chronic hepatitis B or non-B, non-C patients. The RLH pathway activation was downregulated by HCV elimination. In conclusion, HCV infection activated RLH pathway and suppressed HBV replication in human hepatocytes. HCV elimination upregulated HBV replication, probably through RLH pathway downregulation.

Highlights

Mechanisms of hepatitis B virus (HBV) reactivation after hepatitis C virus (HCV) elimination by directacting antiviral (DAA) treatment in HBV/HCV-co-infected patients remain unclear
To examine the influence of HBV and HCV on the RIGI-like helicase (RLH) system, we investigated the expression levels of RIG-I and downstream ISG15 and ISG56 in PHHs
The mRNA levels of RIG-I were slightly higher in HBV-infected cells just after HBV inoculation than in non-infected cells, and no difference was found in ISG15 and ISG56 expression between the two groups of cells (Fig. 1G)

Summary

Introduction

Mechanisms of hepatitis B virus (HBV) reactivation after hepatitis C virus (HCV) elimination by directacting antiviral (DAA) treatment in HBV/HCV-co-infected patients remain unclear. HCV infection activated RLH pathway and suppressed HBV replication in humanized-liver mice. Subsequent elimination of HCV by DAA administration downregulated RLH pathway and upregulated HBV replication in mice. HCV infection activated RLH pathway and suppressed HBV replication in human hepatocytes. Clinical observations have shown that most HBV/HCV-co-infected patients have a lower titre of serum HBV DNA than HBV-mono-infected patients[6,7] It remains unclear whether interference between HBV and HCV exists in co-infected individuals. In approximately 20–30% of hepatitis B surface (HBs) antigen-positive HBV/HCV-co-infected patients, treatment for HCV with direct-acting antivirals (DAAs) causes HBV reactivation[8,9,10,11]. We reveal that HCV infection enhances the RIG-I-like helicase (RLH) system and suppresses HBV replication during HBV/HCV co-infection and that HCV elimination by DAA therapy decreases RLH system induction and enhances HBV replication

Methods

Results

Conclusion