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Journal of Virology, April 2003, p. 4205-4220, Vol. 77, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.7.4205-4220.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Global Changes in Kaposi's Sarcoma-Associated Virus Gene Expression Patterns following Expression of a Tetracycline-Inducible Rta Transactivator

Hiroyuki Nakamura,1 Michael Lu,2 Yousang Gwack,1 John Souvlis,1 Steven L. Zeichner,2* and Jae U. Jung1*

Department of Microbiology and Molecular Genetics, Division of Tumor Virology, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772,1 HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208922

Received 16 October 2002/ Accepted 18 December 2002

An important step in the herpesvirus life cycle is the switch from latency to lytic reactivation. In order to study the life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV), we developed a gene expression system in KSHV-infected primary effusion lymphoma cells. This system uses Flp-mediated efficient recombination and tetracycline-inducible expression. The Rta transcriptional activator, which acts as a molecular switch for lytic reactivation of KSHV, was efficiently integrated downstream of the Flp recombination target site, and its expression was tightly controlled by tetracycline. Like stimulation with tetradecanoyl phorbol acetate (TPA), the ectopic expression of Rta efficiently induced a complete cycle of viral replication, including a well-ordered program of KSHV gene expression and production of infectious viral progeny. A striking feature of Rta-mediated lytic gene expression was that Rta induced KSHV gene expression in a more powerful and efficient manner than TPA stimulation, indicating that Rta plays a central, leading role in KSHV lytic gene expression. Thus, our streamlined gene expression system provides a novel means not only to study the effects of viral gene products on overall KSHV gene expression and replication, but also to understand the natural viral reactivation process.

* Corresponding author. Mailing address: HIV and AIDS Malignancy Branch, NCI Bldg. 10, Room 10S255, MSC 1868, Bethesda, MD 20892-1868. Phone: (301) 402-3637. Fax: (301) 480-8250. E-mail: zeichner{at}nih.gov.

* Corresponding author. Mailing address: Division of Tumor Virology, NERPRC, Harvard Medical School, 1 Pine Hill Dr., Southborough, MA 01772. Phone: (508) 624-8083. Fax: (508) 786-1416. E-mail: jae_jung{at}hms.harvard.edu.

Journal of Virology, April 2003, p. 4205-4220, Vol. 77, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.7.4205-4220.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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