Hepatitis C Virus modulates TNFα-induced chemokine production and enables EGF to induce chemokine production in its host cell

The hepatitis C virus is one of the leading causes of chronic liver diseases worldwide. The creeping course of disease which sometimes takes decades until overt disease indicates that HCV has developed powerful mechanisms enabling the virus to manipulate antiviral immunity and the inflammatory host response and to utilize the infrastructure of the host and the host cell without largely affecting its viability. As they are major determinants of the composition of immune cells present in an organ or in tissue, chemokines play a key role for the orchestration of the inflammatory and the immune response. Hence it is well conceivable that in particular viruses, which establish a persistent infection such as HCV, have gained access to the control of the expression of these mediators.

In the present study the influence of HCV on chemokine production in response to inflammatory or growth stimuli such as TNFα or EGF has been examined using Huh7 cells harbouring the subgenomic HCV replicon (genotype 1b) or Huh7.5 cells infected with the HCVcc strain JC1 (genotype 2a). Thereby the production of chemokines such as CXCL-1 or CXCL-8 induced by TNFα was significantly enhanced in the presence of the HCV replication complex. Most interestingly, however, was the observation that apart from enhancing TNFα-induced chemokine expression, the presence of the HCV replication complex or infection of Huh7.5 cells with the HCVcc strain JC1, even rendered factors such as EGF, which under normal conditions does not or only weekly induce the production of chemokines such as CXCL1 or CXCL8, into strong inducers of the expression of these chemokines. Inhibitor studies using AG1478, a specific inhibitor of EGF receptor (EGFR) tyrosine kinase activity and U0126 an inhibitor of the mitogen protein kinase (MAPK) kinase (MEK)1, suggests that enhanced chemokine expression depends on the activation of EGFR, which is significantly enhanced in the presence of HCV, and requires activation of MEK1. In summary these data provide evidence, that in its host cell HCV has substantial impact on the release of mediators that mediate the intercellular communication and control recruitment of immune cells. Thereby, HCV not only enhances production of chemokines such as CXCL1 and CXCL8 in response to inflammatory mediators but also enables factors such as the growth factor EGF to induce expression of these chemokines. Since these chemokines are involved in e.g. the recruitment of neutrophils this would result in an extension of the conditions under which these cells become recruited to the liver of HCV infected individuals.