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Journal of Virology, November 2005, p. 13984-13992, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.13984-13992.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Lytic Infection Is Required for Efficient Production of the Angiogenesis Factor Vascular Endothelial Growth Factor in Lymphoblastoid Cell Lines

Gregory K. Hong,1,2 Pawan Kumar,3 Ling Wang,1,2 Blossom Damania,1,2 Margaret L. Gulley,4 Henri-Jacques Delecluse,5 Peter J. Polverini,3 and Shannon C. Kenney1,2,6*

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 27599,1 Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 27599,2 Department of Oral Medicine/Pathology/Oncology, 5205 School of Dentistry, 1011 N. University Ave., University of Michigan School Of Dentistry, Ann Arbor, Michigan 48108,3 Department of Pathology, 913 Brinkhous-Bullit, CB #7525, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 27599,4 German Cancer Research Center, Applied Tumour Virology F-100, Im Neuenheimer Feld 242, D-69120, Heidelberg, Germany,5 Department of Medicine, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 275996

Received 10 May 2005/ Accepted 15 August 2005

Although Epstein-Barr virus (EBV)-associated malignancies are primarily composed of cells with one of the latent forms of EBV infection, a small subset of tumor cells containing the lytic form of infection is often observed. Whether the rare lytically infected tumor cells contribute to the growth of the latently infected tumor cells is unclear. Here we have investigated whether the lytically infected subset of early-passage lymphoblastoid cell lines (LCLs) could potentially contribute to tumor growth through the production of angiogenesis factors. We demonstrate that supernatants from early-passage LCLs infected with BZLF1-deleted virus (Z-KO LCLs) are highly impaired in promoting endothelial cell tube formation in vitro compared to wild-type (WT) LCL supernatants. Furthermore, expression of the BZLF1 gene product in trans in Z-KO LCLs restored angiogenic capacity. The supernatants of Z-KO LCLs, as well as supernatants from LCLs derived with a BRLF1-deleted virus (R-KO LCLs), contained much less vascular endothelial growth factor (VEGF) in comparison to WT LCLs. BZLF1 gene expression in Z-KO LCLs restored the VEGF level in the supernatant. However, the cellular level of VEGF mRNA was similar in Z-KO, R-KO, and WT LCLs, suggesting that lytic infection may enhance VEGF translation or secretion. Interestingly, a portion of the vasculature in LCL tumors in SCID mice was derived from the human LCLs. These results suggest that lytically infected cells may contribute to the growth of EBV-associated malignancies by enhancing angiogenesis. In addition, as VEGF is a pleiotropic factor with effects other than angiogenesis, lytically induced VEGF secretion may potentially contribute to viral pathogenesis.

* Corresponding author. Mailing address: 22-038 Lineberger Comprehensive Cancer Center, CB #7295, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 966-1248. Fax: (919) 966-8212. E-mail: shann{at}med.unc.edu.

Journal of Virology, November 2005, p. 13984-13992, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.13984-13992.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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