Impact of alcohol on hepatitis C virus replication and interferon signaling

Abstract

Hepatitis C virus (HCV) is one of the main etiological factors responsible for liver disease worldwide. It has been estimated that there are over 170 million people infected with HCV worldwide. Of these infected individuals, approximately 75% will go on to develop a life long necroinflammatory liver disease, which over decades, can result in serious complications, such as cirrhosis and hepatocellular carcinoma. Currently there is no effective vaccine and whilst antiviral therapies have been improved, they are still only effective in approximately 50% of individuals. HCV infection stands as a major cause of global morbidity and suffering, and places a significant burden on health systems. The second highest cause of liver disease in the western world is alcoholic liver disease. Frequently, HCV infected individuals consume alcohol, and the combined effect of HCV and alcohol consumption is deleterious for both liver disease and response to treatment. This review discusses the impact of alcohol metabolism on HCV replication and the negative impact on interferon (IFN)-alpha treatment, with a particular focus on how alcohol and HCV act synergistically to increase oxidative stress, ultimately leading to exacerbated liver disease and a reduction in the efficacy of IFN-alpha treatment. A better understanding of the complicated mechanisms at play in hepatocytes infected with HCV and metabolizing alcohol will hopefully provide better treatment options for chronic hepatitis C individuals that consume alcohol.

Figure 1

Proposed model of hepatitis C virus (HCV)/alcohol interactions in hepatocytes. Metabolism of alcohol by cytochrome P450-2E1 (CYP2E1) and HCV replication leads to a synergistic induction of oxidative stress in the cell. Oxidative stress inhibits interferon (IFN)-α signalling and also leads to increased rates of inflammation, cirrhosis, and hepatocellular carcinoma (HCC). NS5A: Non-structural 5A; NF-κB: Nuclear factor κB; ROS: Reactive oxygen species.

Figure 2

IFN-α signal transduction. Binding of IFN-α to its cognate receptor on the cell surface results in activation of the Janus activated kinase (JAK)/STAT signaling pathway culminating in the production of interferon-stimulated genes (ISGs), many of which have anti-viral properties that act to limit HCV infection. Alcohol inhibits Y701, decreases interferon-stimulated response element (ISRE) activity, and subsequently dampens the ISG response.