Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression

Hepatitis B virus (HBV) causes chronic hepatitis in hundreds of millions of people worldwide, which can eventually lead to hepatocellular carcinoma (HCC). The molecular mechanisms underlying HBV persistence are not well understood. TRAIL, the TNF-related apoptosis-inducing ligand, has recently been implicated in hepatocyte death during HBV infection. We report here that the HBV core protein (HBc) is a potent inhibitor of TRAIL-induced apoptosis. Overexpressing HBc significantly decreased TRAIL-induced apoptosis of human hepatoma cells, whereas knocking-down HBc expression in hepatoma cells transfected with HBV genome enhanced it. When present in the same cell, HBc blocked the pro-apoptotic effect of the HBV X protein (HBx). The resistance of HBc-expressing cells to TRAIL-induced apoptosis was associated with a significant reduction in death receptor 5 (DR5) expression. Upon transfection, HBc significantly repressed the promoter activity of the human DR5 gene. Importantly, HBc gene transfer inhibited hepatocyte death in a mouse model of HBV-induced hepatitis; and in patients with chronic hepatitis, DR5 expression in the liver was significantly reduced. These results indicate that HBc may prevent hepatocytes from TRAIL-induced apoptosis by blocking DR5 expression, which in turn contributes to the development of chronic hepatitis and HCC. They also call into question the potential side effects of HBc-based vaccines.