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Journal of Virology, February 2003, p. 2631-2639, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2631-2639.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Like Tumors in a Human Herpesvirus 8 ORF74 Transgenic Mouse

Hong-Guang Guo,1 Mariola Sadowska,1 William Reid,1 Erwin Tschachler,2 Gary Hayward,3 and Marvin Reitz1*

Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201,1 Viral Oncology Program, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21231; and Department of Dermatology, University of Vienna Medical School,3 Ludwig Boltzmann Institute for Studies of Venero-Dermatological Infectious Diseases, Vienna A1090, Austria2

Received 1 July 2002/ Accepted 18 November 2002

The product of human herpesvirus 8 (HHV-8) open reading frame 74 (ORF74) is related structurally and functionally to cellular chemokine receptors. ORF74 activates several cellular signaling pathways in the absence of added ligands, and NIH 3T3 cells expressing ORF74 are tumorigenic in nude mice. We have generated a line of transgenic (Tg) mice with ORF74 driven by the simian virus 40 early promoter. A minority (approximately 30%) of the Tg mice, including the founder, developed tumors resembling Kaposi's sarcoma (KS) lesions, which occurred most typically on the tail or legs. The tumors were highly vascularized, had a spindle cell component, expressed VEGF-C mRNA, and contained a majority of CD31+ cells. CD31 and VEGF-C are typically expressed in KS. Tumors generally (but not always) occurred at single sites and most were relatively indolent, although several mice developed large visceral tumors. ORF74 was expressed in a minority of cells in the Tg tumors and in a few other tissues of mice with tumors; mice without tumors did not express detectable ORF74 in any tissues tested. Cell lines established from tumors expressed ORF74 in a majority of cells, expressed VEGF-C mRNA, and were tumorigenic in nude mice. The resultant tumors grew rapidly, metastasized, and continued to express ORF74. Cell lines established from these secondary tumors also expressed ORF74 and were tumorigenic. These data strongly suggest that ORF74 plays a role in the pathology of KS and confirm and extend previous findings on the tumorigenic potential of ORF74.

* Corresponding author. Mailing address: Institute for Human Virology, University of Maryland Biotechnology Institute, 725 W. Lombard St., Baltimore, MD 21201. Phone: (410) 706-4679. Fax: (410) 706-4694. E-mail: reitz{at}umbi.umd.edu.

Journal of Virology, February 2003, p. 2631-2639, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2631-2639.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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