Hepatitis C virus infection and apoptosis

Abstract

Apoptosis is central for the control and elimination of viral infections. In chronic hepatitis C virus (HCV) infection, enhanced hepatocyte apoptosis and upregulation of the death inducing ligands CD95/Fas, TRAIL and TNFalpha occur. Nevertheless, HCV infection persists in the majority of patients. The impact of apoptosis in chronic HCV infection is not well understood. It may be harmful by triggering liver fibrosis, or essential in interferon (IFN) induced HCV elimination. For virtually all HCV proteins, pro- and anti-apoptotic effects have been described, especially for the core and NS5A protein. To date, it is not known which HCV protein affects apoptosis in vivo and whether the infectious virions act pro- or anti-apoptotic. With the availability of an infectious tissue culture system, we now can address pathophysiologically relevant issues. This review focuses on the effect of HCV infection and different HCV proteins on apoptosis and of the corresponding signaling cascades.

Figure 1

Signal transduction pathway of apoptosis in hepatocytes. Immune cells induce apoptosis in hepatocytes by death receptor ligands (TRAIL, TNFα, CD95Ligand, TGF-β) and granzyme B/perforin. Ligand-induced apoptosis activates caspase-8, whereas intrinsic apoptosis occurs via the mitochondrial permeability transition (PT) pore and activation of caspase-9. Caspase-9 and -8 activation converge in activation of the effector caspases-3, -6 and -7, resulting in irreversible apoptosis induction. HSC: Hepatic stellate cells; KC: Kupffer cells; CTL: Cytotoxic T-lymphocytes; NK: Natural killer cells.

Figure 2

Interference of HCV proteins with the apoptosis cascade. Pro- and anti-apoptotic effects of HCV proteins converge at the mitochondria (e.g., NS2, NS3/4A, NS5A, E2, core), partly indirectly via p53 (NS5A, core) and activation of PKB/Akt, c-Jun kinase JNK (core) or NFκB (NS5A). HCV interacts directly with death receptors (core), the corresponding death receptor domains (FADD) and caspase-8 (NS5A). HCV double-strand RNA-activated protein-kinase R (PKR) induced signaling via RIG-I (retinoic acid inducible gene-I) and Cardif is directly (E2, NS5A) and indirectly (NS3/4A) disturbed.