VIRUS-CELL INTERACTIONS IN HEPATITIS B VIRUS REPLICATION AND PATHOGENESIS

Hepatitis B virus (HBV) represents a significant human pathogen, with over 300 million people infected worldwide. Chronic HBV infection not only results in fatal liver diseases such as cirrhosis and liver failure but also dramatically increases the risk of liver cancer by over 100-fold. HBV infections present a fascinating system to study mechanisms of viral replication, virus-host interaction, and viral pathogenesis. HBV replicates a peculiar circular DNA genome via a reverse transcription pathway that is similar to, yet distinct from, that of retroviruses. The outcome of HBV infection ranges from transient, self-resolving acute hepatitis to life-long viral persistence with or without apparent liver pathology and its attendant sequelae. Viral clearance or persistence is clearly determined by the intricate interplay of a multitude of still largely undefined viral and host factors. We are focusing our studies on the virus-host interactions, at the molecular and cellular level, which are critical to HBV replication and pathogenesis.

On the one hand, cellular factors required for viral assembly and replication are being sought using established cell-free as well as cell culture systems. We have identified some of the host factors required during the early stages of viral assembly and reverse transcription. We are continuing these studies in order to elucidate the requirements for the different stages of the viral replication cycle. A defining feature of HBV, as a pararetrovirus, is the fact that only the mature nucleocapsids containg the double-stranded DNA genome are enveloped and secreted extracellularly as virions, whereas the immature nucleocapsids containing the viral RNA or DNA intermediates are not secreted. We have recently discovered that viral reverse transcription and nucleocapsid maturation are coupled to virion secretion through dynamic phosphorylation and dephophorylation of the nucleocapsids. We are in the process of identifying the cellular factors responsible for this process and elucidating its regulation.

On the other hand, we are seeking to identify host factors that may be involved in mediating the clearance of HBV infections, including cell intrinsic antiviral defense mechanism, which may suggest novel ways of curing HBV infections. Our recent results suggest the existence of cellular factors that can block the very early stage of viral assembly and reverse transcription and we are now pursuing the isolation of these cellular inhibitors of HBV replication. We have also obtained evidence that both the viral nucleocapsids and the episomal viral DNA genome are subject to intracellular turnover and we are in the process of elucidating these intracellular antiviral pathways.

By focusing our efforts on the critical host factors that either positively or negatively affects viral replication, persistence and pathogenesis, we hope to eventually manipulate these factors therapeutically with novel antivirals, thus helping to control HBV infection and its deadly consequences. Furthermore, we hope to gain insights into the normal functions of these cellular factors by using viruses as tools.