Polymorphisms in RIG-I like helicases and their influence on the course of Hepatitis C Virus infection

Abstract

Hepatitis C is a major cause of liver cirrhosis, liver failure and hepatocellular carcinoma in humans. Hepatitis C Virus (HCV) infects about 3% of the human population. Interestingly the course of infection varies widely among patients. Approximately 15–20% of the infected individuals clear the infection spontaneously, whereas in 80% the infection presides in a chronic state. Virus-related factors and clinical risk factors of the host such as sex, alcohol consumption and age at infection do not allow to predict the development of a chronic status. It is therefore suspected that the susceptibility to chronic HCV infection is determined by genetic polymorphisms in the host's immune system. The RIG-I like helicase (RLH) RIG-I was recently shown to be responsible for triggering the innate immune response after infection with HCV in cell culture systems. This led us to examine single nucleotide polymorphisms (SNPs) in RIG-I and other components of the RIG-I-like helicase pathway and correlate them with the outcome after HCV-infection. We focused our analysis on non-synonymous SNPs in coding regions and found in a european population that the SNP rs3747517 in Mda-5 (leading to mutation H843R) has a significantly higher prevalence in individuals that spontaneously resolved HCV infection as compared to chronically infected patients. In addition we made expression constructs of RLHs and analysed in complementary in vitro assays the functional consequences of the mutations caused by the analysed SNPs. Together these results suggest an important role of RLHs for the clinical outcome of an HCV infection.