HEPATITIS-B VIRUS HBX PROTEIN SENSITIZES CELLS TO APOPTOTIC KILLING BY TUMOR-NECROSIS-FACTOR-ALPHA

Persistent infection with hepatitis B virus (HBV) is a leading: cause of human liver disease and is strongly associated with hepatocellular carcinoma, one of the most prevalent forms of human cancer. Apoptosis (programmed cell death) is an important mediator of chronic liver dise ase caused by HBV infection. It is demonstrated that the HBV HBx prote in acutely sensitizes cells to apoptotic killing when expressed during viral replication in cultured cells and in transfected cells independ ently of other HBV genes. Cells that were resistant to apoptotic killi ng by high doses of tumor necrosis factor alpha (TNF alpha), a cytokin e associated with liver damage during HEV infection, were made sensiti ve to very low doses of TNF alpha by HBx. HBx induced apoptosis br pro longed stimulation of N-Myc and the stress-mediated mitogen-activated- protein kinase kinase 1 (MEKK1) pathway but not bg up-regulating TNF r eceptors, Cell killing was blocked by inhibiting HBx stimulation of N- Myc off mitogen-activated-protein kinase kinase I using dominant-inter fering forms or by retargeting HBx from the cytoplasm to the nucleus, which prevents HBx activation of cytoplasmic signal transduction casca des. Treatment of cells with a mitogenic growth Factor produced by man y virus-induced tumors impaired induction of apoptosis by HBx and TNF alpha. These results indicate that HBx might be involved in HBV pathog enesis (liver disease) during virus infection and that enhanced apopto tic killing by HBx and TNF alpha might select for neoplastic hepatocyt es that survive by synthesizing mitogenic growth factors.