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Journal of Virology, June 2007, p. 6068-6078, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02743-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication in Primary Effusion Lymphomas ^,¶

Dongsheng Xu,^1, Tricia Coleman,^1,, Jun Zhang,^1,, Ashley Fagot,³ Catherine Kotalik,² Lingjun Zhao,⁵ Pankaj Trivedi,⁶ Clinton Jones,^1,4 and Luwen Zhang^1,2*

Nebraska Center for Virology,¹ School of Biological Sciences,² Department of Biochemistry,³ Department of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, Nebraska 68588,⁴ Institute for Molecular Virology, Saint Louis University, St. Louis, Missouri 63110,⁵ Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Experimental Medicine and Pathology, University of Rome, La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy⁶

Received 13 December 2006/ Accepted 9 March 2007

The majority of AIDS-associated primary effusion lymphomas (PEL) are latently infected with both Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). PELs harboring two viruses have higher oncogenic potential, suggesting functional interactions between EBV and KSHV. The KSHV replication and transcription activator (K-RTA) is necessary and sufficient for induction of KSHV lytic replication. EBV latent membrane protein 1 (LMP-1) is essential for EBV transformation and establishment of latency in vitro. We show EBV inhibits chemically induced KSHV lytic replication, in part because of a regulatory loop in which K-RTA induces EBV LMP-1 and LMP-1 in turn inhibits K-RTA expression and furthermore the lytic gene expression of KSHV. Suppression of LMP-1 expression in dually infected PEL cells enhances the expression of K-RTA and lytic replication of KSHV upon chemical induction. Because LMP-1 is known to inhibit EBV lytic replication, KSHV-mediated induction of LMP-1 would potentiate EBV latency. Moreover, KSHV infection of EBV latency cells induces LMP-1, and K-RTA is involved in the induction. Both LMP-1 and K-RTA are expressed during primary infection by EBV of KSHV latency cells. Our findings provide evidence that an interaction between EBV and KSHV at molecular levels promotes the maintenance and possibly establishment of viral latency, which may contribute to pathogenesis of PELs.

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* Corresponding author. Mailing address: E141 Beadle Center, Nebraska Center for Virology, University of Nebraska, 1901 Vine St., Lincoln, NE 68588. Phone: (402) 472-5905. Fax: (402) 472-8722. E-mail: lzhang2{at}unlnotes.unl.edu

Published ahead of print on 21 March 2007.

^¶ Supplemental material for this article may be found at http://jvi.asm.org/.

These authors contributed equally to this work.

Current address: Abbott Laboratories, 200 Abbott Park Road, Abbott Park, IL 66064.

Current address: Monsanto Company, 800 N. Lindbergh Blvd., St. Louis, MO 63167.

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Journal of Virology, June 2007, p. 6068-6078, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02743-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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