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Journal of Virology, November 2006, p. 10802-10812, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00673-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells Activates Hypoxia-Induced Factors{triangledown}

Patrick A. Carroll,1 Heidi L. Kenerson,2 Raymond S. Yeung,2 and Michael Lagunoff1*

Department of Microbiology,1 Department of Surgery, University of Washington, 1959 Pacific Street, Seattle, Washington 981952

Received 3 April 2006/ Accepted 17 August 2006

Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is the etiological agent of Kaposi's sarcoma, a highly vascularized, endothelial-derived tumor. A direct role for KSHV-mediated induction of angiogenesis has been proposed based upon the nature of the neoplasia and various KSHV gene overexpression and infection model systems. We have found that KSHV infection of endothelial cells induces mRNA of hypoxia-induced factor 1{alpha} (HIF1{alpha}) and HIF2{alpha}, two homologous alpha subunits of the heterodimeric transcription factor HIF. HIF is a master regulator of both developmental and pathological angiogenesis, composed of an oxygen-sensitive alpha subunit and a constitutively expressed beta subunit. HIF is classically activated posttranscriptionally with hypoxia, leading to increased protein stability of HIF1{alpha} and/or HIF2{alpha}. However, we demonstrate that both alpha subunits are up-regulated at the transcript level by KSHV infection. The transcriptional activation of HIF leads to a functional increase in HIF activity under normoxic conditions, as demonstrated by both luciferase reporter assay and the increased expression of vascular endothelial growth factor receptor 1 (VEGFR1), an HIF-responsive gene. KSHV infection synergizes with hypoxia mimics and induces higher expression levels of HIF1{alpha} and HIF2{alpha} protein, and HIF1{alpha} is increased in a significant proportion of the latently infected endothelial cells. Src family kinases are required for the activation of HIF and the downstream gene VEGFR1 by KSHV. We also show that KS lesions, in vivo, express elevated levels of HIF1{alpha} and HIF2{alpha} proteins. Thus, KSHV stimulates the HIF pathway via transcriptional up-regulation of both HIF alphas, and this activation may play a role in KS formation, localization, and progression.

* Corresponding author. Mailing address: Department of Microbiology, University of Washington, 1959 N.E. Pacific Street, Seattle, WA 98195. Phone: (206) 616-4285. Fax: (206) 543-8297. E-mail: Lagunoff{at}u.washington.edu.

{triangledown} Published ahead of print on 6 September 2006.

Journal of Virology, November 2006, p. 10802-10812, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00673-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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