Overcoming CD8+ T-Cell Exhaustion in Viral Hepatitis: Lessons from the Mouse Model and Clinical Perspectives

About 500 million people all over the world are chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV) and are thus at high risk of developing liver fibrosis, cirrhosis or hepatocellular carcinoma. While in adults about 90% of acutely HBV-infected patients clear the virus, only 30% of acute HCV infections clear spontaneously. Several mechanisms contribute to the failure in viral clearance. The main factors responsible for the chronification of HBV and HCV infection are, on the one hand, viral escape mutations leading to lack of recognition by antiviral immune cells and, on the other hand, loss of antiviral effector functions of virus-specific CD8+ T cells, called T-cell exhaustion. This review focuses on the latter highlighting current knowledge about the heterogeneity of exhausted CD8+ T cells and the potential for re-invigoration of exhausted T-cell populations during chronic viral hepatitis. Although direct-acting antivirals successfully clear chronic HCV infection, there is still the need for a prophylactic vaccine to prevent primary infection. Moreover, a therapeutic strategy eliminating HBV infection still does not exist. A better understanding of T-cell exhaustion and the potential for functional recovery will help to develop new immunotherapeutic approaches for chronic viral hepatitis.