Abstract
More than 350 million people worldwide have been persistently infected with the hepatitis B virus (HBV). Chronic HBV infection could advance toward liver cirrhosis and hepatocellular carcinoma. The intervention with prophylactic vaccine and conventional treatment could suppress HBV, but could not completely eradicate it. The major obstacle for investigating curative antiviral drugs are the incompetence of hepatocyte models that should have closely imitated natural human infection. Here, we demonstrated that an immortalized hepatocyte-like cell line (imHC) could accommodate for over 30 days the entire life cycle of HBV prepared from either established cultured cells or clinically-derived fresh isolates. Normally, imHCs had intact interferon signaling with anti-viral action. Infected imHCs responded to treatments with direct-acting antiviral drugs (DAAs) and interferons (IFNs) by diminishing HBV DNA, the covalently closed circular DNA (cccDNA) surface antigen of HBV (HBsAg, aka the Australia antigen) and the hepatitis B viral protein (HBeAg). Notably, we could observe and quantify HBV spreading from infected cells to naïve cells using an imHC co-culture model. In summary, this study constructed a convenient HBV culture model that allows the screening for novel anti-HBV agents with versatile targets, either HBV entry, replication or cccDNA formation. Combinations of agents aiming at different targets should achieve a complete HBV eradication.
Highlights
Hepatitis B virus (HBV) infection is a worldwide threat with more than 2 billion infected individuals that would give rise to 350 million chronic hepatitis B virus (HBV) carriers
We previously developed immortalized hepatocyte-like cells derived from human mesenchymal stem cells [39]
The precursor cells of immortalized human hepatocyte came from human mesenchymal stem cells (hMSCs) that had been immortalized with human telomerase reverse transcriptase and Bmi-1 prior to the differentiation [45]
Summary
Hepatitis B virus (HBV) infection is a worldwide threat with more than 2 billion infected individuals that would give rise to 350 million chronic HBV carriers. Chronic HBV infection risks the development of liver cirrhosis and hepatocellular carcinoma with approximately 620,000 HBV-related deaths annually [1,2]. Current approved treatment comprises only nucleoside analogs (NAs) and interferon-α (IFN-α). These treatments significantly reduced the HBV viral load in patients. NAs, including entecavir (ETV), lamivudine, telbivudine and tenofovir, suppress HBV replication by targeting viral reverse transcriptase. IFN-α indirectly suppresses HBV through modulating the host immune response and directly interferes with HBV replication in hepatocytes [3,4].
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