Multi-omic Analyses Reveal Complex Interactions Between HCV and Hepatocytes Demonstrating That the Red Queen Is Up and Running

Hepatitis C virus treatment with direct‐acting antivirals induces rapid changes in the hepatic proteome

“…Interferon‐stimulated and antiviral proteins were the primary analytes rapidly down‐regulated during treatment. These results are consistent with findings from transcriptomic studies in the liver 17,19,22 and argue translation of ISGs is intact in HCV‐infected liver, contrary to prior observations in cell lines 23,24 . In contrast, we did not identify a proteomic signature suggestive of fibrosis regression when examining known pathways associated with collagen and the ECM (Figure 2).…”

“…The reduction in NFKB and HLA‐DR (Figure 1) correlates with the observed reduction in inflammatory liver cells that occurs due to DAA therapy that likely reflects hepatic egress 45‐47 . In addition, changes in proteins associated with lipid metabolism are consistent with prior transcriptional work from liver biopsies 37 and in vitro analyses examining HCV infection in hepatocyte‐like cell lines 24,49,50 . Although interferon stimulated proteins decreased with treatment, we were unable to distinguish whether these changes were more related to type‐I or type‐III IFN signalling given the overlap in signatures for these two pathways.…”

“…In prior work, we identified transcriptional changes in the liver that occur during HCV treatment with DAAs, including a global down‐regulation of endogenous interferon signalling pathways 17,22 . Previous work suggested the interferon‐associated proteome in the liver may not change in parallel with the interferon‐associated transcriptome, suggesting HCV could impact translation 23,24 . Our long‐term goal is to understand clinically significant changes in the hepatic proteome that can predict the extent of fibrosis regression and which may thus be susceptibility to therapeutic modulation.…”