Hepatitis B virus e antigen in viral persistence

Abstract Hepatitis B virus (HBV) is one of the most important human pathogens. There are approximately 300 million chronic HBV carriers in the world, resulting in nearly 1 million deaths every year. Most chronic HBV carriers acquired the virus from their infected mother early in life. HBV has a very narrow host range, which has greatly hampered its research. By crossing female hemizygous HBV transgenic mice that carry the 1.3mer overlength HBV genome to male naïve mice, we had developed a mouse model to study the mechanism of HBV persistence. We found that the persistence of HBV in mice was dependent on the HBV e antigen (HBeAg) and Kupffer cells, the resident macrophages of the liver. The requirement of HBeAg for HBV persistence is consistent with the clinical observation that the HBV persistence in babies is dependent on the HBeAg-positivity of their mothers. Our recent studies revealed an interesting interplay between HBeAg and hepatic macrophages. This interplay can either promote the HBV persistence or HBV clearance. In this application, we will continue to study this interplay between HBeAg and macrophages to understand the mechanism of HBV persistence. We had recently discovered that HBeAg could reprogram the metabolism of macrophages to promote the oxidative phosphorylation (OXPHOS). This metabolic reprogramming by HBeAg appears to be important for the attenuation of pro-inflammatory activities of Kupffer cells. We will therefore continue to study how HBeAg reprograms the metabolism of macrophages and study the implication of this reprogramming in the anti-HBV response. Our preliminary results also indicated that the toll-like receptor 4 (TLR4) mediated the effects of HBeAg on Kupffer cells. Thus, we will also investigate whether TLR4 serves as the receptor of HBeAg and its role in HBV persistence. Finally, we will determine whether HBeAg by itself is sufficient to promote HBV persistence and whether HBeAg can train Kupffer cells in utero to promote HBV persistence. Our proposed studies will provide important information for us to understand the mechanism of HBV persistence and help to improve the treatments for chronic HBV patients.