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Journal of Virology, October 2007, p. 10249-10257, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00763-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Stabilizes Hypoxia-Inducible Factor 1{alpha} and Stimulates the Synthesis of Vascular Endothelial Growth Factor{triangledown}

Md Nasimuzzaman,1,{dagger} Gulam Waris,1,{dagger},{ddagger} David Mikolon,2 Dwayne G. Stupack,2 and Aleem Siddiqui1*

Department of Medicine, Division of Infectious Diseases, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0711,1 Department of Pathology and Moore's Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, California 92093-08032

Received 9 April 2007/ Accepted 3 July 2007

Hepatitis C virus (HCV) infection is one of the major causes of chronic hepatitis, liver cirrhosis, which subsequently leads to hepatocellular carcinoma (HCC). The overexpression of the angiogenic factors has been demonstrated in HCC. In this study, we investigated the potential of HCV gene expression in inducing angiogenesis. Our results show that HCV infection leads to the stabilization of hypoxia-inducible factor 1{alpha} (HIF-1{alpha}). We further show that this stabilization was mediated via oxidative stress induced by HCV gene expression. The activation of NF-{kappa}B, STAT-3, PI3-K/AkT, and p42/44 mitogen-activated protein kinase was necessary for HIF-1{alpha} stabilization. HIF-1{alpha} induction in turn led to the stimulation of vascular endothelial growth factor. By using the chick chorioallantoic membrane assay, we show that HCV-infected cells released angiogenic cytokines, leading to neovascularization in vivo. These results indicate the potential of HCV gene expression in angiogenesis.

* Corresponding author. Mailing address: Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0711. Phone: (858) 822-1750. Fax: (858) 822-1749. E-mail: asiddiqui{at}ucsd.edu

{triangledown} Published ahead of print on 11 July 2007.

{dagger} M.N. and G.W. contributed equally to this study.

{ddagger} Present address: Department of Microbiology and Immunology, The Chicago Medical School, RFUMS, North Chicago, IL 60064.

Journal of Virology, October 2007, p. 10249-10257, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00763-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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