Type III interferon-induced CBF\u03b2 inhibits HBV replication by hijacking HBx

Fengchao Xu,Qingfei Xiao,Na Li,Hong Zhang,Hongxiao Song,Genhong Cheng,Guangyun Tan

doi:10.1038/s41423-018-0006-2

Abstract

Hepatitis B virus (HBV) and its associated chronic infection remain serious health threats worldwide. However, there is still no impactful approach for clinical treatment of hepatitis B patients. Therefore, developing a better understanding of the interactions between HBV and its host is particularly important. HBV infection has been reported to induce type-III but not type-I or type-II interferon (IFN). In this study, we identified CBFβ, an HIV enhancer, as an HBV restriction factor that is specifically induced by type-III IFN in the early stages of HBV infection. Type-III IFN-induced IL-10 played an important role in the production of CBFβ. Interestingly, the interaction between CBFβ- and HBV-encoded regulatory protein X (HBx) enhanced the stability of CBFβ, but notably blocked HBx-mediated promotion of HBV replication. CBFβ expression was lower in HBV patients than in healthy persons, and the addition of serum from HBV patients inhibited CBFβ expression in HepG2 cells. On the contrary, HBV via HBsAg inhibited type-III IFN-induced CBFβ expression and decreased the anti-HBV activity of type-III IFN, suggesting that HBV inhibits antiviral interferon-stimulated gene (ISG) expression and induces IFN resistance. Collectively, our results demonstrate that type-III IFN-triggered and IL-10-induced CBFβ are crucial factors for inhibiting HBV replication, and the HBx–CBFβ–HBsAg axis reveals a new molecular mechanism of interaction between HBV and its hosts.

Highlights

Three-quarters of the world’s population live in areas where there are high levels of hepatitis B virus (HBV) infection
0.01 regulation of Core-binding factor subunit β (CBFβ) in response to HBV infection, with polydAdT and polyIC as controls, we found that CBFβ was significantly upregulated in HepG2 cells transfected with the HBV wholegenome expression plasmid and that it was downregulated in a time-dependent manner (Fig. 1b)
We hypothesized that type-III IFN plays an indispensable role in this process, and we found that CBFβ was an inducible gene of type-III IFN but not type-I or type-II IFN and that IL-10 was crucial in the induction of CBFβ by type-III IFN

Summary

Introduction

Three-quarters of the world’s population live in areas where there are high levels of hepatitis B virus (HBV) infection. Despite the use of HBV vaccination for almost 30 years, 240 million people out of 2 billion HBV-infected people worldwide are chronically infected with HBV and remain at high risk of developing liver cirrhosis and hepatocellular carcinoma (HCC).[1,2] According to the study on the Global Burden of Disease (2010), HBV infection is the tenth leading cause of death, and more than 780,000 patients die each year due to HBV-related diseases.[3] HBV is a partially double-stranded DNA virus that belongs to the Hepadnaviridae family. All HBV viral RNAs are transcribed from HBV covalently closed circular DNA (cccDNA). Following HBV entry into host cells, cccDNA is converted to RNA in the nucleus and acts as an origin for HBV-persistent infections.[4]

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Results

Conclusion