HBV Infection and Apoptosis: Molecular Mechanisms and Clinical Implications

Hepatitis B virus (HBV) infection is a significant global health burden, with over 250 million people estimated to be living with chronic HBV infection worldwide. The long-term occurrence of HBV infection is directly related to the efficiency that the virus accomplishes in modulation of the host cellular pathways, especially apoptosis. Apoptosis is involved in disposal of infected hepatocytes and control of spreading virus, whereas its disregulation results in chronic infection, hepatitis, fibrosis/cirrhosis, HCC. This review outlines our current understanding of the molecular pathways of apoptosis and apoptotic regulatory networks that are targeted by HBV or its viral proteins, as well as discusses clinical relevance of HBV‑induced cell death in liver disease progression. Hepatitis B virus (HBV) infection is still a worldwide health challenge and it causes chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). Virus-mediated regulation of host apoptotic pathways is a key contributor to the pathogenesis of HBV. Apoptosis serves as a double-edged sword in HBV infection: It is critical for immunological clearance of infected hepatocytes, but its long-term perturbation leads to chronic inflammation, liver damage, fibrosis and ultimately to carcinogenesis. This article provides an overview of the basic apoptotic pathways (both intrinsic and extrinsic) and discusses how HBV promotes these processes to establish chronic infection. Special attention is paid to the dual pro- and anti-apoptotic functions provided by the mitochondrial-targeting factor of HBx, including multi-step influences on mitochondrial control, redox regulation, tumor suppression signaling, and pro-survival processes such as NF-κB-regulated pathways and PI3K/Akt. Moreover, the participation of HBV-enveloped and core proteins in ER stress, mitochondrial apoptosis, and immune-mediated apoptosis induced by cytotoxic T lymphocytes (CTLs) are also reviewed. Finally, the clinical relevance of apoptosis dysregulation during chronic HBV infection and hepatocarcinogenesis is emphasized, and novel therapeutic approaches aimed at targeting HBV–apoptosis crosstalk is discussed. Understanding these mechanisms in greater detail could aid toward developing new therapies that strive to reach a functional cure without damaging the liver. HBV continues to replicate in part by modifying the course of hepatocyte apoptosis; controlled cell death pathways can eliminate infected cells, while chronic or erratic apoptosis promotes inflammation/fibrosis/cirrhosis and enhances HCC risk.