This Article Full Text Full Text (PDF) Other Versions of this Article: JVI.01014-06v1 JVI.01014-06v2 80/21/10712    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hwang, I. I. L. Articles by Ohh, M. Search for Related Content PubMed PubMed Citation Articles by Hwang, I. I. L. Articles by Ohh, M.

 Previous Article  |  Next Article 

Journal of Virology, November 2006, p. 10712-10723, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.01014-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Loss of VHL Confers Hypoxia-Inducible Factor (HIF)-Dependent Resistance to Vesicular Stomatitis Virus: Role of HIF in Antiviral Response

Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada,¹ Cancer Research Program and Division of Haematology-Oncology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada²

Received 17 May 2006/ Accepted 16 August 2006

Hypoxia-inducible factor (HIF) is a central regulator of cellular responses to hypoxia, and under normal oxygen tension the catalytic subunit of HIF is targeted for ubiquitin-mediated destruction via the VHL-containing E3 ubiquitin ligase complex. Principally known for its association with oncogenesis, HIF has been documented to have a role in the antibacterial response. Interferons, cytokines with antiviral functions, have been shown to upregulate the expression of HIF-1, but the significance of HIF in the antiviral response has not been established. Here, using renal carcinoma cells devoid of VHL or reconstituted with functional wild-type VHL or VHL mutants with various abilities to negatively regulate HIF as an ideal model system of HIF activity, we show that elevated HIF activity confers dramatically enhanced resistance to vesicular stomatitis virus (VSV)-mediated cytotoxicity. Inhibition of HIF activity using a small-molecule inhibitor, chetomin, enhanced cellular sensitivity to VSV, while treatment with hypoxia mimetic CoCl₂ promoted resistance. Similarly, targeting HIF-2 by RNA interference also enhanced susceptibility to VSV. Expression profiling studies show that upon VSV infection, the induction of genes with known antiviral activity, such as that encoding beta interferon (IFN-ß), is significantly enhanced by HIF. These results reveal a previously unrecognized role of HIF in the antiviral response by promoting the expression of the IFN-ß gene and other genes with antiviral activity upon viral infection.

Published ahead of print on 23 August 2006.

This article has been cited by other articles:

• Gerber, S. A., Pober, J. S. (2008). IFN-{alpha} Induces Transcription of Hypoxia-Inducible Factor-1{alpha} to Inhibit Proliferation of Human Endothelial Cells. J. Immunol. 181: 1052-1062 [Abstract] [Full Text]  
• Bayele, H. K., Peyssonnaux, C., Giatromanolaki, A., Arrais-Silva, W. W., Mohamed, H. S., Collins, H., Giorgio, S., Koukourakis, M., Johnson, R. S., Blackwell, J. M., Nizet, V., Srai, S. K. S. (2007). HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite. Blood 110: 3039-3048 [Abstract] [Full Text]