Infections with hepatitis B and C viruses affect more than 10 percent of the world population and are the most common etiology of chronic liver disease and hepatocellular carcinoma, which is the fourth leading cause of death from cancer in the world. Current therapies for both viruses are less than optimal. While an effective vaccine for HBV is available, the prospect for an HCV vaccine remains elusive. Given the magnitude and severity of both viral infections as a global public health problem, it is imperative to develop and implement effective prophylactic vaccines and better therapeutic regimens. To achieve this goal, we must understand the viral life cycle at the molecular, cellular, and genetic levels, as well as viral mechanisms for productive and persistent infection, virus-host interactions, and host immune responses. The thematic effort of my laboratory focuses on these topics.
While many gaps in our knowledge of HCV 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 possesses 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. Earlier progress in HCV research has been hampered by a lack of robust infectious and replicating cell culture systems and convenient small animal models. The development of in vitro systems including infectious cell cultures affords the opportunity to fully characterize viral replication and virus-cell interactions. SCID/uPA mice transplanted with human hepatocytes susceptible to HCV infection and transgenic mouse models have been useful as small animal models.
We have taken three approaches to study HCV infection and pathogenesis:
- to understand the mechanisms of action of interferon, ribavirin, and the new class of direct-acting antivirals in HCV therapy, and to explore the biological basis of treatment non-response in order to improve current treatment regimen;
- to apply molecular, biochemical, and functional genomic tools to identify and characterize structural and functional interactions between the virus, viral gene products, and the host; and
- to generate novel reagents and tools for developing and evaluating vaccines and antivirals by building and improving on currently available model systems.
For HBV, the replication and virus-host interactions have been studied in great detail and many of the pathways have been elucidated. The availability of culture systems and small animal models has greatly facilitated the elucidation of fundamental knowledge of the virus and the evaluation of vaccine and therapeutic candidates. While the various virologic functions in replication are well known, the roles of interacting cellular factors remain largely undefined. In addition, the viral and host functions for productive and persistent infection in vivo are poorly understood. Among the viral gene products, the accessory proteins HBeAg and HBX are not essential for replication in vitro but appear to be important for viral infection in vivo. HBX has multifarious effects and appears to function through several pathways including signal transduction, transcriptional activation/DNA repair, and/or cellular proteolysis. These mechanisms may not be mutually exclusive and can be concurrently operative in contributing to the pleiotropic effect of HBX. Despite the uncertainty about the mechanism of HBX functions, it has been generally accepted that this gene product is required for the establishment of HBV infection in vivo. We have been focusing on understanding the functions of HBX and developing therapeutic strategy targeting this important viral function. We are also applying our overall approach in functional genomics described above for HCV to studying HBV-host interactions.