Host response to hepatitis C virus
Authors: Sabine Mihm
Journal: Hepatology (2005)

To the Editor: In their recent study published in HEPATOLOGY, Major et al.1 analyzed a panel of host responses to a hepatitis C virus (HCV) infection in chimpanzees. The authors investigated innate immune responses by examining oligoadenylate synthetase expression as a surrogate for type I interferon (IFN)-regulated processes, intrahepatic cytokine expression with interleukin 10 (IL-10) and IFN-γ as surrogates for T-lymphocyte or natural killer (NK) cell activation, intrahepatic chemokine expression, and the presence of CD3+ lymphocytes within the liver. By closely monitoring the serum viral load and carrying out kinetic analyses, they were able to decipher 3 phases of virus-host interactions: an acute phase of infection with unimpeded virus replication, an early post-acute phase with a reduced replication rate, and a third phase which was marked by a decrease in viral titers. The authors observed the deceleration in the viral replication to be associated with the onset of a type I IFN response and the declining virus titer to be correlated with increased IFN-γ expression in all animals. The parameters that they assumed to be relevant for resolving the infection, however, were (1) an earlier onset of the host immune response indicated by an increase in ALT activity, and (2) an intrahepatic CD3e and macrophage inflammatory protein 1 alpha (MIP-1α) messenger RNA induction. We find this comprehensive view on the host parameters to be particularly noteworthy because it gives innate, humoral, and cellular immune responses equal attention. Based on our experience, we see some important parallels to the HCV infection in humans and to liver disorders in general. As has been found to be the case in chimpanzees with steady-state levels of viral titers, livers of chronic hepatitis C patients also contain elevated levels of IFN-γ transcripts.2, 3 Through combined immunohistochemical means and in situ hybridization, IFN-γ messenger RNA was demonstrated to be localized in CD3+ lymphocytes infiltrating portal tracts and hepatic lobules.4 In contrast to the human HCV-infected liver, however, livers of persistently infected chimpanzees are generally poorly infiltrated. Active hepatitis in persistent infection is rarely manifested; which, of note, is also the case with some human HCV carriers.5 This poor infiltration is reflected in lower intrahepatic CD3e+ messenger RNA levels in persistently infected animals compared with those animals that eliminated the virus. As suggested by Major et al., the source(s) of IFN-γ transcripts should thus be different. In the former group of animals it should be the NK cells, and in the latter group of animals it should be either the infiltrating T lymphocytes or both the NK cells and T lymphocytes. This assumption reflects a recent observation made on an animal model of acute toxic liver injury, in which IFN-γ expression was found to occur in two different instances: (1) in the acute injury phase before the start of cellular infiltration, and (2) in the post-acute injury phase with prominent inflammation.6 In human chronic HCV carriers, the clearance of HCV RNA can also occur during a superinfection with the hepatitis B virus (HBV).7, 8 We were able to monitor serological parameters for one such patient, who successfully resolved both infections.7 With the detectability of hepatitis B surface antigen (HBsAg), serum alanine aminotransferase (ALT) activity rose. In accordance with what has been observed in chimpanzees, we also noted an increase in the IFN-γ expression. This increase coincided with both the temporal increase in serum ALT and aspartate aminotransferase (AST) activities and the loss of HCV RNA. In contrast, disappearance of HBsAg took place later with the onset of an anti-HBsAg antibody response. Sabine Mihm Ph.D.*, * Department of Gastroenterology, Georg-August-Universität, Göttingen, Germany.