Epstein–Barr virus (EBV) replicates in superficial differentiated cells of oral hairy leukoplakia (OHL). Differentiation of squamous epithelial cells depends on B-lymphocyte-induced maturation protein 1 (Blimp1). Here we show that expression of the EBV immediate-early protein BZLF1 is restricted to Blimp1-positive epithelial cells in OHL. Luciferase assays revealed Blimp1-dependent induction of the BZLF1 promoter Zp in epithelial cell lines. Expression of ZEB1, a negative regulator of Zp, and of Xbp-1, which mediates the Blimp1 effect on Zp in B-cells, was not affected by enforced Blimp1 expression. Moreover, Xbp-1 protein expression was not detected in differentiated epithelial cells of OHL. Thus, Blimp1 induces BZLF1 expression in epithelial cells independently of ZEB1 and Xbp-1. In contrast to epithelial cells of OHL, BZLF1 expression was also observed in Blimp1-negative lymphoid cells in infectious mononucleosis tonsils, suggesting that EBV replication in B-cells may be induced independently of terminal differentiation.
Al TabaaY., TuaillonE., JeziorskiE., OuedraogoD. E., BolloréK., RubboP. A., FoulongneV., RodièreM., VendrellJ. P.2011; B-cell polyclonal activation and Epstein–Barr viral abortive lytic cycle are two key features in acute infectious mononucleosis. J Clin Virol 52:33–37 [View Article][PubMed]
BhendeP. M., DickersonS. J., SunX., FengW. H., KenneyS. C.2007; X-box-binding protein 1 activates lytic Epstein–Barr virus gene expression in combination with protein kinase D. J Virol 81:7363–7370 [View Article][PubMed]
BinnéU. K., AmonW., FarrellP. J.2002; Promoter sequences required for reactivation of Epstein–Barr virus from latency. J Virol 76:10282–10289 [View Article][PubMed]
ChangD. H., CattorettiG., CalameK. L.2002; The dynamic expression pattern of B lymphocyte induced maturation protein-1 (Blimp-1) during mouse embryonic development. Mech Dev 117:305–309 [View Article][PubMed]
EllisA. L., WangZ., YuX., MertzJ. E.2010; Either ZEB1 or ZEB2/SIP1 can play a central role in regulating the Epstein–Barr virus latent-lytic switch in a cell-type-specific manner. J Virol 84:6139–6152 [View Article][PubMed]
FrangouP., BuettnerM., NiedobitekG.2005; Epstein–Barr virus (EBV) infection in epithelial cells in vivo: rare detection of EBV replication in tongue mucosa but not in salivary glands. J Infect Dis 191:238–242 [View Article][PubMed]
GreenspanJ. S., GreenspanD., LennetteE. T., AbramsD. I., ConantM. A., PetersenV., FreeseU. K.1985; Replication of Epstein–Barr virus within the epithelial cells of oral “hairy” leukoplakia, an AIDS-associated lesion. N Engl J Med 313:1564–1571 [View Article][PubMed]
KarimiL., CrawfordD. H., SpeckS., NicholsonL. J.1995; Identification of an epithelial cell differentiation responsive region within the BZLF1 promoter of the Epstein–Barr virus. J Gen Virol 76:759–765 [View Article][PubMed]
LinK. I., Angelin-DuclosC., KuoT. C., CalameK.2002; Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol Cell Biol 22:4771–4780 [View Article][PubMed]
MagnúsdóttirE., KalachikovS., MizukoshiK., SavitskyD., Ishida-YamamotoA., PanteleyevA. A., CalameK.2007; Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1. Proc Natl Acad Sci U S A 104:14988–14993 [View Article][PubMed]
MontalvoE. A., CottamM., HillS., WangY. J.1995; YY1 binds to and regulates cis-acting negative elements in the Epstein–Barr virus BZLF1 promoter. J Virol 69:4158–4165[PubMed]
MurrayP. G., NiedobitekG., KremmerE., GrässerF., ReynoldsG. M., CruchleyA., WilliamsD. M., Müller-LantzschN., YoungL. S.1996; In situ detection of the Epstein–Barr virus-encoded nuclear antigen 1 in oral hairy leukoplakia and virus-associated carcinomas. J Pathol 178:44–47 [View Article][PubMed]
RabanusJ. P., GreenspanD., PetersenV., LeserU., WolfH., GreenspanJ. S.1991; Subcellular distribution and life cycle of Epstein–Barr virus in keratinocytes of oral hairy leukoplakia. Am J Pathol 139:185–197[PubMed]
RooneyC. M., RoweD. T., RagotT., FarrellP. J.1989; The spliced BZLF1 gene of Epstein–Barr virus (EBV) transactivates an early EBV promoter and induces the virus productive cycle. J Virol 63:3109–3116[PubMed]
Shapiro-ShelefM., LinK. I., McHeyzer-WilliamsL. J., LiaoJ., McHeyzer-WilliamsM. G., CalameK.2003; Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19:607–620 [View Article][PubMed]
ThomasC., DankesreiterA., WolfH., SchwarzmannF.2003; The BZLF1 promoter of Epstein–Barr virus is controlled by E box-/HI-motif-binding factors during virus latency. J Gen Virol 84:959–964 [View Article][PubMed]