Abstract
The Epstein-Barr virus (EBV) latent-lytic switch is mediated by the BZLF1 immediate-early protein. EBV is normally latent in memory B cells, but cellular factors which promote viral latency specifically in B cells have not been identified. In this report, we demonstrate that the B-cell specific transcription factor, Oct-2, inhibits the function of the viral immediate-early protein, BZLF1, and prevents lytic viral reactivation. Co-transfected Oct-2 reduces the ability of BZLF1 to activate lytic gene expression in two different latently infected nasopharyngeal carcinoma cell lines. Furthermore, Oct-2 inhibits BZLF1 activation of lytic EBV promoters in reporter gene assays, and attenuates BZLF1 binding to lytic viral promoters in vivo. Oct-2 interacts directly with BZLF1, and this interaction requires the DNA-binding/dimerization domain of BZLF1 and the POU domain of Oct-2. An Oct-2 mutant (Δ262–302) deficient for interaction with BZLF1 is unable to inhibit BZLF1-mediated lytic reactivation. However, an Oct-2 mutant defective for DNA-binding (Q221A) retains the ability to inhibit BZLF1 transcriptional effects and DNA-binding. Importantly, shRNA-mediated knockdown of endogenous Oct-2 expression in several EBV-positive Burkitt lymphoma and lymphoblastoid cell lines increases the level of lytic EBV gene expression, while decreasing EBNA1 expression. Moreover, treatments which induce EBV lytic reactivation, such as anti-IgG cross-linking and chemical inducers, also decrease the level of Oct-2 protein expression at the transcriptional level. We conclude that Oct-2 potentiates establishment of EBV latency in B cells.
Highlights
Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis and is widely prevalent within the human population, infecting greater than 90% of all individuals [1,2]
Memory B cells serve as the primary reservoir of latent EBV infection, while oropharyngeal epithelial cells support the lytic form of infection [1,2,4,5,6,7,8]
Memory B cells are the primary site of EBV latency within the human host, while oropharyngeal epithelial cells support the lytic form of infection
Summary
Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis and is widely prevalent within the human population, infecting greater than 90% of all individuals [1,2]. Memory B cells serve as the primary reservoir of latent EBV infection, while oropharyngeal epithelial cells support the lytic form of infection [1,2,4,5,6,7,8]. EBV can be reactivated to the lytic form when infected memory B cells, stimulated by antigen, differentiate into plasma cells [9]. While both the latent and lytic forms of infection are essential for the long-term success of EBV, the specific cellular factors that determine the very different outcomes following EBV infection in B cells versus epithelial cells remain poorly defined
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