The B-cell specific transcription factor, Oct-2, promotes Epstein-Barr virus latency by inhibiting the viral immediate-early protein, BZLF1

PLoS Pathog. 2012 Feb;8(2):e1002516. doi: 10.1371/journal.ppat.1002516. Epub 2012 Feb 9.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • B-Lymphocytes / virology*
  • Cell Line, Tumor
  • Epstein-Barr Virus Infections / virology
  • Gene Expression Regulation, Viral / genetics
  • Gene Knockdown Techniques
  • Herpesvirus 4, Human / physiology*
  • Humans
  • Octamer Transcription Factor-2 / genetics
  • Octamer Transcription Factor-2 / metabolism*
  • PAX5 Transcription Factor / genetics
  • PAX5 Transcription Factor / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Multimerization
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Virus Activation
  • Virus Latency*

Substances

  • BZLF1 protein, Herpesvirus 4, Human
  • Octamer Transcription Factor-2
  • PAX5 Transcription Factor
  • Trans-Activators