Hepatitis C virus infection results in a reorganization of the expression pattern of ErbB receptor family members on its host cell

The Hepatitis C Virus is one of the leading causes for chronic liver disease. According to the WHO, there are round about 150 million people infected all over the world and more than 70% of them establish a chronic infection with ongoing viral replication. There are 3 – 4 million new infections every year, 350,000 people die annually from Hepatitis C related liver diseases and approximately 5 – 20% of all infected people develop liver cirrhosis and 1 – 5% die from liver cirrhosis or hepatocellular carcinoma.

In most cases the disease proceeds asymptomatic over decades without being recognized, suggesting that the virus evolved the ability to circumvent antiviral immunity, to influence the inflammatory host response and to utilize the infrastructure of the host without affecting host cell viability.

Recent work indicates that HCV interferes with the EGF receptor (also termed as ErbB1) and its activation. Hence, EGFR acts as a cofactor for viral entry into its host cell and is activated by HCV, which has been demonstrated to be critical for virus entry and replication. The activation of EGFR is even further enhanced by HCV-mediated degradation of the T-cell protein tyrosine phosphatase (TC-PTP) that acts as an endogenous negative regulator of EGFR activity. Apart from EGFR, the ErbB receptor family comprises three additional members termed as ErbB2, ErbB3 and ErbB4. In how far HCV also interferes with the other family members of the EGFR family is unclear. A question which has been addressed in the present study. Analysis of the influence of HCV on the expression of the different ErbB family members revealed that, compared to control conditions, expression of EGFR and ErbB2 is not affected or even enhanced in cells harbouring the subgenomic replicon of HCV genotype 1b or cells infected with the HCVcc strain JC1, whereas the expression of ErbB3 and ErbB4 is down-regulated to 50% and 10%, respectively. Further experiments suggest that in particular the effect of HCV on ErbB3 expression involves activation of the transcription factor Sp1 and cAMP since it can be mimicked by up-regulation of cAMP expression or transfection of Sp1. Considering that under normal conditions ErbB3 is highly expressed on hepatocytes these data provide evidence that HCV has substantial impact on the expression pattern of EGFR family members on its host cell shifting it towards a pattern with pre-dominant expression of EGFR and ErbB2. This observation may be part of the measures induced by HCV to adapt and optimize cellular infrastructure to its own requirements.