Transcriptional response to hepatitis C virus infection and interferon‐alpha treatment in the human liver

Hepatitis C virus (HCV) is widely used to investigate host–virus interactions. Cellular responses to HCV infection have been extensively studied in vitro . However, in human liver, interferon (IFN)‐stimulated gene expression can mask direct transcriptional responses to infection. To better characterize the direct effects of HCV infection in vivo , we analyze the transcriptomes of HCV‐infected patients lacking an activated endogenous IFN system. We show that expression changes observed in these patients predominantly reflect immune cell infiltrates rather than cell‐intrinsic pathways. We also investigate the transcriptomes of patients with endogenous IFN activation, which paradoxically cannot eradicate viral infection. We find that most IFN‐stimulated genes are induced by both recombinant IFN therapy and the endogenous IFN system, but with lower induction levels in the latter, indicating that the innate immune response in chronic hepatitis C is too weak to clear the virus. We show that coding and non‐coding transcripts have different expression dynamics following IFN treatment. Several microRNA primary transcripts, including that of miR‐122, are significantly down‐regulated in response to IFN treatment, suggesting a new mechanism for IFN‐induced expression fine‐tuning. Synopsis The molecular effects of HCV infection and interferon alpha (IFN‐α) treatment in the human liver are not yet fully understood. HCV‐infected patients have variable responses to IFN‐α therapy. Paradoxically, patients with an endogenous IFN system activation do not respond to recombinant IFN therapy. In patients with low endogenous levels of IFN‐stimulated genes, the transcriptional response to viral infection predominantly reflects immune cell infiltrates. In patients with endogenous IFN system activation, transcriptional patterns are qualitatively similar to the response to recombinant IFN therapy. These patients show lower levels of gene induction compared to recombinant IFN therapy, indicating that the innate immune response is too weak to clear the virus. Several miRNA primary transcripts, including pri‐miR‐122, are down‐regulated by IFN therapy, suggesting a new mechanism for IFN‐induced expression fine‐tuning. Graphical Abstract The molecular effects of HCV infection and interferon alpha (IFN‐α) treatment in the human liver are not yet fully understood. HCV‐infected patients have variable responses to IFN‐α therapy. Paradoxically, patients with an endogenous IFN system activation