Does the interferon-lambda rather than the interferon-alpha pathway determine the outcome of hepatitis C virus infection?

The molecular mechanisms that link IFN-lambda 3 genotypes to differential induction of interferon (IFN)-stimulated genes (ISGs) in the liver of patients with chronic hepatitis C (CHC) are not known. We measured the expression of IFN-lambda and of the specific IFN-lambda receptor chain (IFN-lambda R1) in 122 liver biopsies of patients with CHC and 53 control samples. The IFN-lambda 3 genotype was not associated with differential expression of IFN-lambda, but rather IFN-lambda R1. In a series of 30 primary human hepatocyte (PHH) samples, IFN-lambda R1 expression was low but could be induced with IFN-alpha. IFN-alpha-induced IFN-lambda R1 expression was significantly stronger in PHHs carrying the minor IFN-lambda 3 allele. The analysis of liver biopsies of patients with CHC revealed a strong association of high IFN-lambda R1 expression with elevated ISG expression, with IFN-lambda 3 minor alleles, and with nonresponse to pegylated IFN-alpha and ribavirin. The findings provide a missing link between the IFN-lambda 3 genotype and the associated phenotype of treatment nonresponse.