Drug modulators of B cell signaling pathways and Epstein-Barr virus lytic activation

John G. Kosowicz, Jaeyeun Lee, Brandon Peiffer, Zufeng Guo, Jianmeng Chen, Gangling Liao, S. Diane Hayward, Jun O. Liu, Richard F. Ambinder

Research output: Contribution to journalArticlepeer-review

Abstract

Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction. Further investigation shows that mammalian target of rapamycin complex 2 (mTORC2) contributes to BCR-mediated lytic induction and that FK506-binding protein 12 (FKBP12) binding alone is not adequate to block activation. Finally, we show that BCR signaling can activate EBV lytic induction in freshly isolated B cells from peripheral blood mononuclear cells (PBMCs) and that activation can be inhibited by ibrutinib or idelalisib.

Original languageEnglish (US)
Article numbere00747-17
JournalJournal of virology
Volume91
Issue number16
DOIs
StatePublished - Aug 1 2017

Keywords

  • B cell receptor pathway
  • Cyclosporine
  • Dasatinib
  • Epstein-Barr virus
  • Ibrutinib
  • Idelalisib
  • Lytic infection
  • MTOR
  • Rapamycin
  • Tacrolimus

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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