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Journal of Virology, January 2010, p. 647-660, Vol. 84, No. 1
0022-538X/10/$012.00+0     doi:10.1128/JVI.00769-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus-Linked Mitochondrial Dysfunction Promotes Hypoxia-Inducible Factor 1-Mediated Glycolytic Adaptation ^,

Maria Ripoli,¹ Annamaria D'Aprile,¹ Giovanni Quarato,¹ Magdalena Sarasin-Filipowicz,² Jérôme Gouttenoire,³ Rosella Scrima,¹ Olga Cela,¹ Domenico Boffoli,¹ Markus H. Heim,² Darius Moradpour,³ Nazzareno Capitanio,¹ and Claudia Piccoli^1*

Department of Biomedical Sciences, University of Foggia, Foggia, Italy,¹ Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland,² Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland³

Received 16 April 2009/ Accepted 9 October 2009

Hepatitis C virus (HCV) infection induces a state of oxidative stress by affecting mitochondrial-respiratory-chain activity. By using cell lines inducibly expressing different HCV constructs, we showed previously that viral-protein expression leads to severe impairment of mitochondrial oxidative phosphorylation and to major reliance on nonoxidative glucose metabolism. However, the bioenergetic competence of the induced cells was not compromised, indicating an efficient prosurvival adaptive response. Here, we show that HCV protein expression activates hypoxia-inducible factor 1 (HIF-1) by normoxic stabilization of its subunit. In consequence, expression of HIF-controlled genes, including those coding for glycolytic enzymes, was significantly upregulated. Similar expression of HIF-controlled genes was observed in cell lines inducibly expressing subgenomic HCV constructs encoding either structural or nonstructural viral proteins. Stabilization and transcriptional activation of HIF-1 was confirmed in Huh-7.5 cells harboring cell culture-derived infectious HCV and in liver biopsy specimens from patients with chronic hepatitis C. The HCV-related HIF-1 stabilization was insensitive to antioxidant treatment. Mimicking an impairment of mitochondrial oxidative phosphorylation by treatment of inducible cell lines with oligomycin resulted in stabilization of HIF-1. Similar results were obtained by treatment with pyruvate, indicating that accumulation of intermediate metabolites is sufficient to stabilize HIF-1. These observations provide new insights into the pathogenesis of chronic hepatitis C and, possibly, the HCV-related development of hepatocellular carcinoma.

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* Corresponding author. Mailing address: Department of Biomedical Sciences, University of Foggia, Via L. Pinto 1-OO.RR.-71100 Foggia, Italy. Phone: 39-0881-711148. Fax: 39-0881-714745. E-mail: c.piccoli{at}unifg.it

Published ahead of print on 21 October 2009.

Supplemental material for this article may be found at http://jvi.asm.org/.

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Journal of Virology, January 2010, p. 647-660, Vol. 84, No. 1
0022-538X/10/$012.00+0     doi:10.1128/JVI.00769-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved.