PNNL

Abstract

We previously employed systems biology approaches to identify the mitochondrial fatty acid oxidation enzyme dodecenoyl-CoA delta isomerase (DCI) as a bottleneck protein controlling metabolic reprogramming during hepatitis C virus (HCV) infection. Here we present the results of studies confirming the importance of DCI to HCV pathogenesis. HCV growth and RNA replication in hepatoma cell lines stably expressing DCI-targeting short hairpin RNA (shRNA) were abrogated, indicating that DCI is required for productive infection. Pharmacologic inhibition of fatty acid oxidation also blocked HCV replication. Production of infectious HCV was restored by overexpression of a shRNA-resistant DCI allele. Sophisticated computational models incorporating proteomic data from HCV patient liver biopsies recapitulated our original predictions regarding DCI and link HCV-associated alterations in cellular metabolism and liver disease progression. These findings demonstrate the utility of systems biology approaches to gain novel insight into the biology of HCV infection and identify translationally relevant novel therapeutic targets.