MOLECULAR PATHOGENESIS OF HEPATITIS B VIRUS AND HEPATITIS C VIRUS INFECTIONS

Abstract

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections cause a wide range of liver diseases including hepatocellular carcinoma (HCC) worldwide. Because these two viruses have the same modes of transmission, HBV HCV co-infections are found in approximately 7 to 20 million people globally. HBV HCV co-infections are associated with more severe liver diseases and higher risk of HCC. Previous studies have established that HBV and HCV mono-infection can cause hepatic steatosis, and steatosis is a confirmed risk factor for HCC. However, whether and how HBV HCV co-infections synergistically increase the risk of HCC development through modulating lipid metabolism is not well understood. PTEN is a phosphatase which contains both lipid and protein phosphatase activities. PTEN acts as a tumor suppressor by down-regulating the phosphoinositide-3-kinase (PI3K)/Akt/ sterol regulatory element-binding protein (SREBP) signaling pathway. It has been reported that PTEN is frequently mutated or deleted in tumors including HCC. PTEN-Long, a longer isoform of PTEN, which is able to be exported into the extracellular compartments, enter neighboring cells, and induce signaling events in recipient cells. Both HBV and HCV infections can inhibit PTEN and activate SREBP. However, how regulation of PTEN/SREBP pathway affects HBV and HCV infections is not fully understood. Therefore, the effect of the PTEN/SREBP pathway on HBV and/or HCV infections is worthy to study. In this study, we showed that both HBV X protein (HBx) and HCV core protein regulate PTEN/SREBP pathway. We established that HBx activates SREBP-1a and SREBP-1c through different mechanisms. This process is involved in up-regulating of HBV enhancer I or HBV enhancer II. We demonstrated multiple mechanisms of how HBx regulates HBV replication. We also showed that HCV core interacts with PTEN and PTEN-Long which is involved in regulating of HCV life cycle. In an HBV HCV co-infection cellular model, HBx and HCV core have similar regulatory effects on the PTEN/SREBP pathway as in mono-infections. However, PTEN and SREBP differentially regulate HBV and HCV replication in HBV HCV co-infection.