Minicircle DNA vector expressing interferon-lambda-3 inhibits hepatitis B virus replication and expression in hepatocyte-derived cell line

Xiaoyan Guo,Qingxian Cai,Wenxiong Xu,Liang Peng,Dianke Chen,Zhanlian Huang,Ping Chen

doi:10.1186/s12860-020-00250-9

Abstract

BackgroundInterferon-alpha (IFNα) is a first-line treatment option for chronic hepatitis B virus (HBV) infection, but the severe systemic side-effects limited its clinical application. Interferon-lambda (IFNλ) with comparable antiviral activity and less toxic side-effects is thought to be a good alternative interferon to IFNα. Additionally, the gene vector mediated sustainably expression of therapeutic product in the target cells/tissue may overcome the shortcomings resulted from the short half-life of IFNs.ResultsWe constructed a liver-specific IFNλ3-expressing minicircle (MC) vector under the control of a hepatocyte-specific ApoE promoter (MC.IFNλ3) and investigated its anti-HBV activity in a HBV-expressing hepatocyte-derived cell model (HepG2.2.15). As expected, the MC.IFNλ3 vector capable of expressing IFNλ3 in the recipient hepatocytes has demonstrated robust anti-HBV activity, in terms of suppressing viral antigen expression and viral DNA replication, via activation the interferon-stimulated gene (ISG) expression in HepG2.2.15 cells.ConclusionsGiven the MC vector can be easily delivered into liver, the liver-targeted IFN gene-transfer (MC.IFNλ3), instead of systemic administrating IFN repeatedly, provides a promising concept for the treatment of chronic HBV infection.

Highlights

Interferon-alpha (IFNα) is a first-line treatment option for chronic hepatitis B virus (HBV) infection, but the severe systemic side-effects limited its clinical application
We determined the expression of IFNα or IFNλ3 in a variety of cell lines after 3 days of transfection with MC.IFNs by Western blot, including in HepG2.2.15, HEK293 and Hela (Cervical squamous cell) cell lines
Little or no IFNα/IFNλ3 signal was detected in MC transfected HEK293 or Hela cells while clear and strong protein signal was shown in the HepG2.2.15 cells transfected with MC.IFNα (Fig. 1b upper row, Lane 2) or MC.IFNλ3 (Fig. 1b middle row, Lane 3), illustrating the MC.IFNs constructs permit hepatocyte-specific expression of interferons

Summary

Introduction

Interferon-alpha (IFNα) is a first-line treatment option for chronic hepatitis B virus (HBV) infection, but the severe systemic side-effects limited its clinical application. There are no cures for chronic hepatitis B (CHB), as the current treatments including the nucleos(t) ide analogues (NAs) and interferon-alpha (IFNα) therapy do not effectively clear HBV from the infected individuals [3]. According to the interim results report, a significant (2-log) HDV-RNA decline was observed in majority of patients, while the adverse side-effects typically seen with INFα were fewer [19, 22]. These studies suggest that IFNλ may be a good alternative treatment against HBV infection

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Results

Conclusion