Expression data from primary human hepatocyte oxygenated co-cultures infected by HCV and human liver biopsies from HCV patients.

Viruses lack the basic machinery needed to replicate and therefore must hijack host metabolism to propagate. Virus-induced metabolic alterations have yet to be systematically studied in the context of the host transcriptional regulation, offering insight into host-pathogen metabolic interplay. In this work we identified Hepatitis C Virus (HCV)-responsive regulators by coupling system-wide metabolic flux analysis with targeted perturbation of nuclear receptors in primary human hepatocytes. We find HCV-induced up-regulation of glycolysis, ketogenesis and drug metabolism, controlled by activation of HNF4, PPAR, FXR and PXR, respectively. Pharmaceutical inhibition of HNF4 reversed HCV-induced glycolysis, blocking viral replication while increasing apoptosis in infected cells showing a viral-induced dependence on glycolysis. In contrast, pharmaceutical inhibition of PPAR or FXR reversed HCV-induced ketogenesis, but increased viral replication demonstrating a unique host anti-viral response. Our results show that viral-induced changes to host metabolism can be detrimental to its lifecycle demonstrating a distinct biological complexity.

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Levy G, Habib N, Guzzardi MA, Kitsberg D, Bomze D, Ezra E, Uygun BE, Uygun K, Trippler M, Schlaak JF, Shibolet O, Sklan EH, Cohen M, Timm J, Friedman N, Nahmias Y