Hepatitis B virus persistence in mice reveals IL-21 and IL-33 as regulators of viral clearance

Zhongliang Shen,Junqi Zhang,Wei Wang,Xiaoxian Cui,Xian Zhou,Shaokun Pan,Wei Liu,Jing Liu,Yanfeng Liu,Huijuan Yang,Jiming Zhang,Sisi Yang,Youhua Xie

doi:10.1038/s41467-017-02304-7

Zhongliang Shen, Junqi Zhang + Show 11 more

Open Access

https://doi.org/10.1038/s41467-017-02304-7

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Abstract

Hepatitis B virus (HBV) generally causes self-limiting infection in immunocompetent adults, but establishes chronic infection in some adults and in most maternally infected infants. Factors determining clearance versus persistence are not fully understood. Hydrodynamic injection (HDI) of HBV replicon plasmid via tail vein generally results in quick clearance in immunocompetent adult mice. Here, we report the identification of strain-specific persistence of HBV in mice: one genotype B strain, designated BPS, persisted up to 33 weeks in ~50% of HDI mice. BPS persistence requires viral replication and multiple viral features. Compared to quickly cleared strains, BPS fails to induce robust post-exposure serum IL-21/IL-33 responses. Injection of IL-21-expressing or IL-33-expressing plasmids facilitates clearance of pre-established BPS persistence and protects cured mice from BPS re-challenge. IL-21 and IL-33 also induce clearance of pre-established HBV persistence in another mouse model. These data reveal IL-21 and IL-33 as potent regulators of HBV clearance and valid drug candidates.

Highlights

Hepatitis B virus (HBV) generally causes self-limiting infection in immunocompetent adults, but establishes chronic infection in some adults and in most maternally infected infants
A panel of common non-B genotype strains displayed similar quick clearance of HBsAg (Supplementary Fig. 3). These results agreed with previous data showing that HBV replicon plasmids without associated virus (AAV)-derived sequences could not persist in immunocompetent mice[12]
Unlike previously reported mouse models of HBV persistence, BPS persists in common immunocompetent mice without requiring non-HBV viral elements

Summary

Introduction

Hepatitis B virus (HBV) generally causes self-limiting infection in immunocompetent adults, but establishes chronic infection in some adults and in most maternally infected infants. Recent data linked age-dependent high chronicity rate in young mice to lower HBV-dependent IL-21 production[8,9] and immature gut microbiota[10] In comparison, such models have offered fairly limited information on HBV persistence in adults, mostly because adult mice of common immunocompetent strains, including BALB/c and C57BL/6, clear HBV serum markers very quickly after HBV genome plasmids were delivered via hydrodynamic injection (HDI)[11,12,13]. Relative persistence in naïve immunocompetent adult mice has only been observed when adeno-associated virus (AAV)[12] or lentiviral[14] sequences were included in delivery plasmid, or when low doses of recombinant adenovirus[15] or AAV16 vectors were used for delivery These models have enabled studying mechanisms of HBV persistence[17,18,19] and developing novel therapeutics[20], but it’s difficult to evaluate roles played by non-HBV viral elements in the observed effects, either directly or through interplay with HBV and/or host functions. We characterised BPS-based HBV persistence mouse model by attempting to identify persistence-related viral and host factors, which showed IL-21 and IL-33 as potent inducers of HBV clearance and promising drug candidates

Methods

Results

Conclusion