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Journal of Virology, December 2007, p. 13578-13586, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01663-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

X Box Binding Protein XBP-1s Transactivates the Kaposi's Sarcoma-Associated Herpesvirus (KSHV) ORF50 Promoter, Linking Plasma Cell Differentiation to KSHV Reactivation from Latency{triangledown}

Sam J. Wilson,1 Edward H. Tsao,1 Benjamin L. J. Webb,1 Hongtao Ye,2 Lucy Dalton-Griffin,1 Christoforos Tsantoulas,1 Catherine V. Gale,1 Ming-Qing Du,2 Adrian Whitehouse,3 and Paul Kellam1*

Department of Infection, UCL, Cleveland Street, London W1T 4JF,1 Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP,2 Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom3

Received 31 July 2007/ Accepted 28 September 2007

Reactivation of lytic replication from viral latency is a defining property of all herpesviruses. Despite this, the authentic physiological cues for the latent-lytic switch are unclear. Such cues should ensure that viral lytic replication occurs under physiological conditions, predominantly in sites which facilitate transmission to permissive uninfected cells and new susceptible hosts. Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with the B-cell neoplasm primary effusion lymphoma (PEL), in which the virus remains latent. We have previously shown that PEL cells have the gene expression profile and immunophenotype of cycling preplasma cells (plasmablasts). Here, we show that the highly active spliced isoform of plasma cell transcription factor X box binding protein 1 (XBP-1s) is a lytic switch for KSHV. XBP-1s is normally absent in PEL, but the induction of endoplasmic reticulum stress leads to XBP-1s generation, plasma cell-like differentiation, and lytic reactivation of KSHV. XBP-1s binds to and activates the KSHV immediate-early gene ORF50 and synergizes with the ORF50 gene product RTA to induce a full lytic cycle. These data suggest that KSHV remains latent until B-cell terminal differentiation into plasma cells, the transcriptional environment of which provides the physiological "lytic switch" through XBP-1s. This links B-cell terminal differentiation to KSHV lytic reactivation.

* Corresponding author. Mailing address: 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 10 October 2007.

Journal of Virology, December 2007, p. 13578-13586, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01663-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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