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.

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

“…Although recent RNA interference (RNAi) screens targeting a limited number of host factors have already uncovered Glypican 5 (GPC5; [17]) and DNA polymerase kappa (POLK [46]; see below) as new HBV dependency factors, higher throughput applications will require further improvements [92]. …”

Hepatitis B virus sensitivity to interferon‐α in hepatocytes is more associated with cellular interferon response than with viral genotype

“…Here, we produced infectious virions of HBV genotypes A to D to infect three well‐characterized cell–culture–based models . including primary human hepatocytes (PHH), differentiated HepaRG (dHepaRG), and HepG2‐NTCP cells to quantitatively compare the antiviral effect of IFN‐α on HBV across different genotypes in human hepatocytes.…”

“…Here, we produced infectious virions of HBV genotypes A to D to infect three well-characterized cellculture-based models. (16,17) including primary human hepatocytes (PHH), differentiated HepaRG (dHe-paRG), and HepG2-NTCP cells to quantitatively compare the antiviral effect of IFN-a on HBV across different genotypes in human hepatocytes. The results showed that while the inhibitory capacity of IFN-a on HBV replication in HBV-infected cells was generally similar among the four genotypes, it was strikingly different among the three cell-culture-based HBV infection models.…”

Comprehensive Proteomics Identification of IFN-λ3-regulated Antiviral Proteins in HBV-transfected Cells

“…These cells contain a plasmid which expresses the complete genome of HBV, which integrates into host cellular DNA (20,28). Because HBV within HepG2.2.15 replicates and secretes HBsAg, HBeAg and HBV DNA into the culture media, HepG2.2.15 has been widely used as a model of chronic hepatitis B (22,28). The HepG2.2.15 cell line was kindly provided from Professor Antonio Bertoletti (Singapore Institute for Clinical Sciences, A*Star).…”

“…HepG2.2.15 cells (20). HepG2.2.15 cells have been widely used as a model of chronic hepatitis B because they support HBV replication and virion secretion (21)(22)(23)(24)(25)(26)(27). These new findings could improve the treatment strategy of HBV infection and expand potential applications of IFN-3.…”