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Journal of Virology, November 2002, p. 11024-11032, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.11024-11032.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Tissue Specificity of the Kaposi's Sarcoma-Associated Herpesvirus Latent Nuclear Antigen (LANA/orf73) Promoter in Transgenic Mice

Joseph H. Jeong,1 Rebecca Hines-Boykin,1 John D. Ash,2,3,4 and Dirk P. Dittmer1*

Department of Microbiology and Immunology,1 Oklahoma Center for Neuroscience,2 Departments of Ophthalmology,3 Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 731044

Received 22 April 2002/ Accepted 29 July 2002

Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is a human-oncogenic herpesvirus. Cells from KSHV-associated tumors, such as Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), are of endothelial and B-cell origin, respectively. KSHV persists indefinitely in these cell lineages during latent infection. Indeed, cellular latency is a hallmark of all herpesviruses that is intimately linked to their pathogenesis. We previously characterized the promoter for the KSHV latency-associated nuclear antigen LANA/orf73. LANA is required for latent episome maintenance and has also been implicated in oncogenesis. Hence, regulation of LANA expression is critical to KSHV persistence. We find that a region extending to bp -1299 upstream of the LANA transcription start site is able to drive lacZ-reporter gene expression in several lines of transgenic mice. In agreement with KSHV's natural tropism, we detected reporter gene expression in CD19-positive B cells but not in CD3-positive T cells. We also detected expression in the kidney and, at a lower level, in the liver. In contrast to KS tumors, transgene expression was localized to kidney tubular epithelium rather than vascular endothelial cells. This suggests that our promoter fragment contains all cis-regulatory elements sufficient for B-cell specificity but not those required for endothelial specificity. Alternatively, while the trans-acting factors required for LANA expression in B cells are evolutionarily conserved, those that regulate endothelial cell-specific expression are unique to humans. Our in vivo studies address a conundrum in KSHV biology: in culture, KSHV is able to infect a variety of cell types indiscriminately, while in healthy latent carriers KSHV is found in B lymphocytes. The transgenic-mouse experiments reported here suggest that tissue-restricted LANA gene expression could explain B-cell-specific viral persistence.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Oklahoma City, OK 73104. Phone: (405) 271-2690. Fax: (405) 271-3117. E-mail: dirk-dittmer{at}ouhsc.edu.

Journal of Virology, November 2002, p. 11024-11032, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.11024-11032.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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