Cell Culture Models for the Investigation of Hepatitis B and D Virus Infection

Abstract

Chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) infections are major causes of liver disease and hepatocellular carcinoma worldwide. Despite the presence of an efficient preventive vaccine, more than 250 million patients are chronically infected with HBV. Current antivirals effectively control but only rarely cure chronic infection. While the molecular biology of the two viruses has been characterized in great detail, the absence of robust cell culture models for HBV and/or HDV infection has limited the investigation of virus-host interactions. Native hepatoma cell lines do not allow viral infection, and the culture of primary hepatocytes, the natural host cell for the viruses, implies a series of constraints restricting the possibilities of analyzing virus-host interactions. Recently, the discovery of the sodium taurocholate co-transporting polypeptide (NTCP) as a key HBV/HDV cell entry factor has opened the door to a new era of investigation, as NTCP-overexpressing hepatoma cells acquire susceptibility to HBV and HDV infections. In this review, we summarize the major cell culture models for HBV and HDV infection, discuss their advantages and limitations and highlight perspectives for future developments.

Keywords: NTCP; Viral cell entry; hepatocytes; hepatoma cells; life cycle.

Figure 1

Schematic representation of the HBV and HDV life cycles in hepatocytes. HBV: hepatitis B virus; HDV: hepatitis D virus; HDV RNP: HDV ribonucleoprotein. HBV NC: HBV nucleocapsid. rcDNA: relaxed circular DNA. −/+ssRNA: negative/positive single-stranded RNA. cccDNA: covalently closed circular DNA. HBV pgRNA: HBV pregenomic RNA. HDAgs: hepatitis D antigens. HBcAg: HBV core antigen. HBsAg: HBV surface antigen. p: HBV polymerase. HBV SVP: HBV subviral particle. TDP2: tyrosyl-DNA phosphodiesterase 2.