HCV-Mediated Apoptosis of Hepatocytes in Culture and Viral Pathogenesis

Abstract

Chronic Hepatitis C Virus (HCV) infection is associated with progressive liver injury and subsequent development of fibrosis and cirrhosis. The death of hepatocytes results in the release of cytokines that induce inflammatory and fibrotic responses. The mechanism of liver damage is still under investigation but both apoptosis and immune-mediated processes may play roles. By observing the changes in gene expression patterns in HCV-infected cells, both markers and the causes of HCV-associated liver injury may be elucidated. HCV genotype 1b virus from persistently infected VeroE6 cells induced a strong cytopathic effect when used to infect Huh7.5 hepatoma cells. To determine if this cytopathic effect was a result of apoptosis, ultrastructural changes were observed by electron microscopy and markers of programmed cell death were surveyed. Screening of a human PCR array demonstrated a gene expression profile that contained upregulated markers of apoptosis, including tumor necrosis factor, caspases and caspase activators, Fas, Bcl2-interacting killer (BIK) and tumor suppressor protein, p53, as a result of HCV genotype 1b infection. The genes identified in this study should provide new insights into understanding viral pathogenesis in liver cells and may possibly help to identify novel antiviral and antifibrotic targets.

Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19

“…In chronic hepatitis C virus (HCV) infection, Fas expression increases on peripheral blood mononuclear cells (PBMCs), and human hepatocytes are sensitized to TRAIL-induced apoptosis [ 54 ]. This mechanism seems to correlate with liver pathology and fibrogenesis [ 55 , 56 ]. The same effects were observed during the infection with hepatitis B (HBV) [ 57 ].…”

Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells

“…Our study revealed that the expression of HCV proteins in the full-length replicon leads to the activation of both the apoptotic pathways. Previously it was reported that Huh7.5 cells harboring the subgenomic replicon or infected by recombinant variants of the virus in the HCV cell culture (HCVcc) system activated FAS- and TRAIL-mediated outer and inner pathways of apoptosis through the induction of the unfolded protein response, pro-apoptotic Bax protein and cytochrome c release [ 2 , 46 , 48 ]. As the same was observed only for the core protein, this protein has the most pronounced impact on apoptosis induction in HCV-infected cells.…”

Distinct Immune Imprints of Post–Liver Transplantation Hepatitis C Persist Despite Viral Clearance

“…Importantly, one mediator that was uniquely upregulated in HCV+LT patients compared to all other controls was Caspase-8 (CASP-8), a pro-apoptotic protein that may induce apoptosis of the infected hepatocytes. Of note, apoptosis of hepatocytes is one of the ways leading to liver cirrhosis and HCV proteins could directly be involved in apoptosis (34) . In the context of liver transplantation, immunosuppression may facilitate HCV mediated apoptosis of hepatocytes and the subsequent liver fibrosis by impairing immune control of HCV (35).…”