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Journal of Virology, July 2009, p. 7202-7209, Vol. 83, No. 14
0022-538X/09/$08.00+0     doi:10.1128/JVI.00076-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

X-Box Binding Protein 1 Contributes to Induction of the Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycle under Hypoxic Conditions{triangledown}

Lucy Dalton-Griffin,1 Sam J. Wilson,2 and Paul Kellam1,3*

Department of Infection, UCL, Cleveland Street, London W1T 4JF, United Kingdom,1 Aaron Diamond AIDS Research Center, Rockefeller University, 455 First Avenue, New York, New York 10016,2 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom3

Received 13 January 2009/ Accepted 24 April 2009

Kaposi's sarcoma-associated herpesvirus (KSHV), like other herpesviruses, has two stages to its life cycle: latency and lytic replication. KSHV is required for development of Kaposi's sarcoma, a tumor of endothelial origin, and is associated with the B-cell tumor primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman's disease, all of which are characterized by predominantly latent KSHV infection. Recently, we and others have shown that the activated form of transcription factor X-box binding protein 1 (XBP-1) is a physiological trigger of KSHV lytic reactivation in PEL. Here, we show that XBP-1s transactivates the ORF50/RTA promoter though an ACGT core containing the XBP-1 response element, an element previously identified as a weakly active hypoxia response element (HRE). Hypoxia induces the KSHV lytic cycle, and active HREs that respond to hypoxia-inducible factor 1{alpha} are present in the ORF50/RTA promoter. Hypoxia also induces active XBP-1s, and here, we show that both transcription factors contribute to the induction of RTA expression, leading to the production of infectious KSHV under hypoxic conditions.

* Corresponding author. Mailing address: Virus Genomics & Informatics Group, Department of Infection, UCL, 46 Cleveland Street, London W1T 4JF, United Kingdom. Phone: 44 20 7679 9559. Fax: 44 20 7679 9555. E-mail: p.kellam{at}ucl.ac.uk

{triangledown} Published ahead of print on 29 April 2009.

Journal of Virology, July 2009, p. 7202-7209, Vol. 83, No. 14
0022-538X/09/$08.00+0     doi:10.1128/JVI.00076-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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