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X-box binding protein 1 induces the expression of the lytic cycle transactivator of Kaposi's sarcoma-associated herpesvirus but not Epstein–Barr virus in co-infected primary effusion lymphoma

By Imogen Yi-Chun Lai, Paul J. Farrell and Paul Kellam


Cells of primary effusion lymphoma (PEL), a B-cell non-Hodgkin's lymphoma, are latently infected by Kaposi's sarcoma-associated herpesvirus (KSHV), with about 80 % of PEL also co-infected with Epstein–Barr virus (EBV). Both viruses can be reactivated into their lytic replication cycle in PEL by chemical inducers. However, simultaneous activation of both lytic cascades leads to mutual lytic cycle co-repression. The plasma cell-differentiation factor X-box binding protein 1 (XBP-1) transactivates the KSHV immediate–early promoter leading to the production of the replication and transcription activator protein (RTA), and reactivation of KSHV from latency. XBP-1 has been reported to act similarly on the EBV immediate–early promoter Zp, leading to the production of the lytic-cycle transactivator protein BZLF1. Here we show that activated B-cell terminal-differentiation transcription factor X-box binding protein 1 (XBP-1s) does not induce EBV BZLF1 and BRLF1 expression in PEL and BL cell lines, despite inducing lytic reactivation of KSHV in PEL. We show that XBP-1s transactivates the KSHV RTA promoter but does not transactivate the EBV BZLF1 promoter in non-B-cells by using a luciferase assay. Co-expression of activated protein kinase D, which can phosphorylate and inactivate class II histone deacetylases (HDACs), does not rescue XBP-1 activity on Zp nor does it induce BZLF1 and BRLF1 expression in PEL. Finally, chemical inducers of KSHV and EBV lytic replication in PEL, including HDAC inhibitors, do not lead to XBP-1 activation. We conclude that XBP-1 specifically reactivates the KSHV lytic cycle in dually infected PELs

Topics: Animal
Publisher: Society for General Microbiology
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Provided by: PubMed Central

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  1. (1985). Activation of expression of latent Epstein–Barr herpesvirus after gene transfer with a small cloned subfragment of heterogeneous viral DNA.
  2. (2000). Activation of the BRLF1 promoter and lytic cycle of Epstein–Barr virus by histone acetylation.
  3. (2007). B cell terminal differentiation factor XBP-1 induces reactivation of Kaposi’s sarcoma-associated herpesvirus.
  4. (2000). Cells expressing the Epstein-Barr virus growth program are present in and restricted to the naive B-cell subset of healthy tonsils.
  5. (2004). Comparative analysis of signal transduction by CD40 and the Epstein-Barr virus oncoprotein LMP1 in vivo.
  6. (2005). Distinct subsets of primary effusion lymphoma can be identified based on their cellular gene expression profile and viral association.
  7. (2007). Epstein-Barr virus inhibits Kaposi’s sarcoma-associated herpesvirus lytic replication in primary effusion lymphomas.
  8. (2001). Epstein-Barr virus: exploiting the immune system.
  9. (1999). Epstein–Barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients.
  10. (2009). Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes.
  11. (2008). Histone hyperacetylation occurs on promoters of lytic cycle regulatory genes in Epstein-Barr virus-infected cell lines which are refractory to disruption of latency by histone deacetylase inhibitors.
  12. (2005). Human herpesvirus 8 enhances human immunodeficiency virus replication in acutely infected cells and induces reactivation in latently infected cells.
  13. (2002). IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA.
  14. (2007). Kaposi’s sarcoma-associated herpesvirus promotes angiogenesis by inducing angiopoietin-2 expression via AP-1 and
  15. (1997). Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule.
  16. (2004). Lytic cycle gene regulation of Epstein-Barr virus.
  17. (2002). MEF2-mediated recruitment of class II HDAC at the EBV immediate early gene BZLF1 links latency and chromatin remodeling.
  18. (1997). Methylation of the Epstein-Barr virus genome in normal lymphocytes.
  19. (2005). Mutation of a single amino acid residue in the basic region of the Epstein-Barr virus (EBV) lytic cycle switch protein Zta (BZLF1) prevents reactivation of EBV from latency.
  20. (2008). Mutual inhibition between Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr virus lytic replication initiators in dually-infected primary effusion lymphoma.
  21. (2008). Nuclear factor-Y and Epstein–Barr virus in nasopharyngeal cancer.
  22. other authors (2004). Infection of HHV-8+ primary effusion lymphoma cells with a recombinant Epstein-Barr virus leads to restricted EBV latency, altered phenotype, and increased tumorigenicity without affecting TCL1 expression.
  23. other authors (2009). Epstein–Barr virus infection leads to partial phenotypic reversion of terminally differentiated malignant B cells.
  24. other authors (2009). Expression pattern of XBP1(S) in human B-cell lymphomas.
  25. (2005). Peripheral B cells latently infected with Epstein–Barr virus display molecular hallmarks of classical antigenselected memory B cells.
  26. (2004). Persistence of the Epstein– Barr virus and the origins of associated lymphomas.
  27. (2006). PKD at the crossroads of DAG and PKC signaling.
  28. (2001). Plasma cell differentiation requires the transcription factor XBP-1.
  29. (2007). Plasma cell-specific transcription factor XBP-1s binds to and transactivates the EpsteinBarr virus BZLF1 promoter.
  30. (2002). Protein kinase C-independent activation of the Epstein-Barr virus lytic cycle.
  31. (1996). Protein kinase D (PKD) activation in intact cells through a protein kinase C-dependent signal transduction pathway.
  32. (2003). Protein kinase D mediates a stressinduced NF-kB activation and survival pathway.
  33. (2000). Protein kinase D. A selective target for antigen receptors and a downstream target for protein kinase C in lymphocytes.
  34. (1998). Reactivation of Kaposi’s sarcoma-associated herpesvirus infection from latency by expression of the ORF 50 transactivator, a homolog of the EBV R protein.
  35. (2010). Regulation of the Epstein–Barr virus Zp promoter in B lymphocytes during reactivation from latency.
  36. (1997). Selective switch between latency and lytic replication of Kaposi’s sarcoma herpesvirus and Epstein-Barr virus in dually infected body cavity lymphoma cells.
  37. (2002). Signal transduction and transcription factor modification during reactivation of EpsteinBarr virus from latency.
  38. (2005). Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo.
  39. (1992). The cellular oncogene c-myb can interact synergistically with the Epstein–Barr virus BZLF1 transactivator in lymphoid cells. M o lC e l lB i o l12,
  40. (2006). The nuclear import of protein kinase D3 requires its catalytic activity.
  41. (1981). The regulated expression of Epstein– Barr virus. III. Proteins specified by EBV during the lytic cycle.
  42. (1989). The spliced BZLF1 gene of Epstein-Barr virus (EBV) transactivates an early EBV promoter and induces the virus productive cycle.
  43. (2006). Valproic acid enhances the efficacy of chemotherapy in EBV-positive tumors by increasing lytic viral gene expression.
  44. (2006). Virus and cell RNAs expressed during Epstein-Barr virus replication.
  45. (2007). 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.
  46. (2009). X-box binding protein 1 contributes to induction of the Kaposi’s sarcoma-associated herpesvirus lytic cycle under hypoxic conditions.
  47. (2007). X-box-binding protein 1 activates lytic Epstein-Barr virus gene expression in combination with protein kinase D.