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Journal of Virology, December 2008, p. 11902-11912, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01042-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Disrupts Adherens Junctions and Increases Endothelial Permeability by Inducing Degradation of VE-Cadherin{triangledown}

Li-Wu Qian,1,2 Whitney Greene,1,2 Fengchun Ye,1,2 and Shou-Jiang Gao1,2,3,4,5,6*

Tumor Virology Program, Greehey Children's Cancer Research Institute,1 Departments of Pediatrics,2 Microbiology and Immunology,3 Molecular Medicine,4 Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, Texas,5 Tumor Virology Group, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China6

Received 18 May 2008/ Accepted 16 September 2008

Kaposi's sarcoma (KS) is a vascular tumor of proliferative endothelial cells caused by KS-associated herpesvirus (KSHV) infection. Aberrant vascular permeability is a hallmark of KS manifested as multifocal edematous skin and visceral lesions with dysregulated angiogenesis and vast inflammatory infiltrations. In this study, we showed that KSHV infection increased the permeability of confluent endothelial monolayers to serum albumin, blood-derived cells, KSHV-infected cells, and KSHV virions. KSHV-induced permeability was associated with the disruption of adherens junctions and the degradation of vascular endothelial cadherin (VE-cadherin) protein. Both the inactivation of KSHV virions by UV irradiation and the blockage of de novo protein synthesis with cycloheximide failed to reverse the KSHV-induced disruption of adherens junctions. However, soluble heparin that blocked KSHV entry into cells completely inhibited KSHV-induced permeability. Furthermore, the KSHV-induced degradation of VE-cadherin was dose dependent on the internalized virus particles. Together, these results indicate that KSHV infection induces vascular permeability by inducing VE-cadherin degradation during virus entry into cells. KSHV-induced aberrant vascular permeability could facilitate virus spread, promote inflammation and angiogenesis, and contribute to the pathogenesis of KSHV-induced malignancies.

* Corresponding author. Mailing address: Tumor Virology Program, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229. Phone: (210) 562-9030. Fax: (210) 562-9014. E-mail: gaos{at}uthscsa.edu

{triangledown} Published ahead of print on 24 September 2008.

Journal of Virology, December 2008, p. 11902-11912, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01042-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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