Viral hepatitis is a major cause of morbidity and mortality worldwide. Five viruses (hepatitis A-E viruses) are involved. Hepatitis A, B and C viruses predominate. Viruses B (EBV) and C (HCV) are responsible for chronic hepatitis, which can develop into liver cancer. These are distinct classes of hepatotropic viruses, with HBV and HCV capable of very rapid replication. The cycle of these viruses is now fairly well understood, and has led to the development of effective drugs against HCV infection. The kinetics of the onset of immune responses to these viruses are well known. Significantly, the anti-HBV or HCV T response is only detected after two months of infection, and this response is known to cause hepatitis by destroying infected hepatocytes.
The HCV virus brings into play a strong, early innate response through activation of nucleic acid receptors and production of type I interferon. Seemingly paradoxically, one of the type I interferon-induced proteins, USP18, inhibits interferon signaling and is stabilized by ISG15, another interferon-induced protein. This feedback mechanism probably accounts for the poor response to type I interferon therapy in hundreds of HCV-infected patients who also have a genetic predisposition (the variant of a type III interferon that induces less ISG15 production is associated with a good response).
The adaptive T response is also important, as shown by the influence of HLA class I alleles on viral clearance. We know that, in the event of chronic infection, T lymphocytes acquire characteristics that render them incapable of controlling the infection. These are known as "exhausted" T lymphocytes. The high mutation capacity of HCV and the long interval before the development of the T response probably account for the appearance of C viruses that escape the immune response in part. Vaccinations against HAV and HBV have been available for many years. The same cannot be said for HCV, due to the difficulty of obtaining stable, immunizing virus-like particles.
