HBV virology

HBV infection remains a major global public health challenge. Approximately 1.2 million new HBV infections occur annually, and an estimated 254 million people worldwide are living with chronic hepatitis B (CHB). CHB causes approximately 1.1 million deaths each year, primarily as a result of cirrhosis and hepatocellular carcinoma (HCC).

Although currently approved antiviral therapies effectively suppress HBV replication, reduce viral load, and improve clinical outcomes, they rarely achieve a functional cure, defined as sustained off-treatment control of viral replication and loss of hepatitis B surface antigen (HBsAg). The principal limitation of existing therapies is their inability to eliminate covalently closed circular DNA (cccDNA), the highly stable viral replication intermediate that persists within the nuclei of infected hepatocytes. Furthermore, these treatments generally fail to restore robust antiviral immune responses capable of durably controlling residual viral infection.

Accordingly, the primary objectives of our HBV research program are to elucidate the molecular mechanisms governing cccDNA metabolism and functional regulation, as well as to investigate  the immune mechanisms responsible for the epigenetic silencing of cccDNA minichromosome. In addition, the molecular mechanisms of HBV nucleocapsid assembly and reverse transcriptional genome replication are also under investigation.

Flavivirus Infection and Innate Antiviral Immunity

Interferons (IFNs) are central mediators of both innate and adaptive antiviral immunity and play a critical role in limiting viral infection and shaping host defense responses. Over the past two decades, our laboratory has employed forward genetic and functional genomic approaches to identify and characterize multiple interferon-stimulated genes (ISGs) that inhibit the replication of hepatitis C virus (HCV), flaviviruses, and human coronaviruses through distinct molecular mechanisms. Our studies have also revealed unexpected virus-host interactions. Notably, we discovered that human coronavirus OC43 (HCoV-OC43) exploits interferon-induced transmembrane (IFITM) proteins, which are traditionally considered antiviral restriction factors, to facilitate viral entry into host cells. This finding highlights the complex and sometimes paradoxical roles that host antiviral proteins can play during virus infection.

In collaboration with Dr. Jinhong Chang’s laboratory, our current research efforts focus on elucidating the molecular mechanisms by which flaviviruses activate innate immune signaling pathways in infected cells and how these responses contribute to the control of viral infection or infected cell death. We are also investigating the multifunctional roles of the flavivirus NS4B protein in viral genome replication, modulation of host cellular processes, and evasion of innate antiviral immune responses.

Antiviral Drug Discovery and Translational Research

Leveraging the cell-based experimental systems established in our virology and innate immunology studies, we have developed several cell-based assays for the high-throughput screening of antiviral compounds and innate immune agonists. Particularly, these efforts led to the discovery of several chemotypes of HBV capsid assembly modulators (CAMs). One of these compounds, AB-423, advanced to a Phase I clinical trial and provided clinical validation for CAM as a therapeutic strategy for chronic hepatitis B. Building upon this success, and in collaboration with Drs. Yanming Du and Jinhong Chang, we are currently advancing a next-generation HBV CAM with superior antiviral activity, favorable pharmacological and safety profiles through preclinical development. In collaboration with Dr. Jinhong Chang, our drug screening efforts have also led to the discovery of novel STING agonists and a Yellow Fever virus (YFV) NS4B inhibitor. In addition, we are developing siRNA and gene-editing-based therapeutics for the cure of CHB.