U.S. Department of Health and Human Services

Liver Diseases Virology Section

T. Jake Liang, M.D., Chief

About the Section

The Liver Diseases Virology Section focuses on understanding the mechanisms of disease and to improve treatment and prevention of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, a​nd viral hepatitis-associated hepatocellular carcinoma (HCC).

Current Research

Hepatitis B and C viruses together infect more than 10 percent of the world population and are the most common causes of chronic liver disease and hepatocellular carcinoma, which is now the fourth leading cause of death from cancer in the world1. Current therapies for HBV are less than optimal. Recent advances of direct-acting antivirals in HCV therapy have substantially improved the outlook for millions of HCV-infected people. The prospect for a HCV vaccine remains elusive. Given the global public health burden, it is crucial to improve on strategies to control the two infections including more affordable and effective therapies and preventive measures. To achieve this goal, we need to understand viral life cycle, viral mechanisms of productive and persistent infection, and virus-host interactions at the molecular, cellular and genomic levels. The thematic effort of my laboratory focuses on these topics.

While many gaps in our knowledge of HCV still exist, great strides have been made in characterizing the virus and functions of viral genes as well as in unraveling the replication pathway and immunologic mechanisms of liver injury. HCV, like many other viruses, exploits host cellular machinery for productive infection. However, unlike other RNA viruses, HCV has a high propensity to cause persistent infection despite an active host immune response. Thus, it commands unique mechanisms to counteract the various host defenses. HCV gene products have been shown to interact with many host factors and to induce cellular alterations vital for viral replication, persistence and pathogenesis. The development of in vitro systems including infectious cell cultures affords the opportunity to fully characterize viral replication and virus-cell interactions as well as developing novel therapeutics. SCID/uPA mice transplanted with human hepatocytes susceptible to HCV infection and transgenic mouse models expressing human HCV entry factors are useful small animal models.

For HBV, replication and virus-host interactions have been studied extennsively. The availability of HBV culture systems and small animal models has greatly advanced fundamental knowledge of the virus and the evaluation of vaccine and therapeutic candidates. However the complexity of virus-host interactions during HBV infection remains unclear. In addition, chronic infection with both viruses is assoicated with development of hepatocellular carcinoma (HCC) that carries high morbidity and mortality and is difficult to diagnose and treat. Virus-associated HCC remains poorly understood and is an important unmet need in liver diseases.

  1. To study virus-host interactions by applying genome-wide technologies and systems biology approaches.
  2. To apply and develop cutting-edge technologies and model systems to discover novel small molecule probes of HBV and HCV life cycles and to explore them for potential therapeutic advances.
  3. To investigate the mechanisms of action of antiviral therapy and to explore the role of innate immunity in viral pathogenesis and treatment response.

We successful adopted the technology of iPSC and hepatocyte differentiation as in vitro and in vivo models to study HBV and HCV infections. We demonstrated that these differentiated, hepatocyte-like cells (HLCs), despite an immature phenotype, are permissive to HCV infection in vitro and mount an interferon response. The HLCs could be engrafted in the liver parenchyma of immunodeficient mice. The HLCs were maintained for more than 3 months in the liver of the chimeric mouse, where they underwent further maturation and proliferation. These chimeric mice were permissive to infection with HBV and HCV-positive sera of different genotypes and support long-term infection.

Finally, we have established an active research program on the increasingly important problem of hepatocellular carcinoma in the context of chronic viral hepatitis. We are developing various in vitro and in vivo models to identify and study potentially important procarcinogenic pathways that are triggered by HBV or HCV infection. By leveraging this knowledge, we hope to uncover novel strategies for preventive and therapeutic interventions of this deadly cancer.​