Related Experiment Video
Updated: Mar 1, 2026
Generation of Multivirus-specific T Cells to Prevent/treat Viral Infections after Allogeneic Hematopoietic Stem Cell Transplant
Published on: May 27, 2011
Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation
John G Kosowicz1, Jaeyeun Lee1, Brandon Peiffer2
1Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
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.IMPORTANCE EBV establishes viral latency in B cells. Activation of the B cell receptor pathway activates lytic viral expression in cell lines. Here we show that drugs that inhibit important kinases in the BCR signaling pathway inhibit activation of lytic viral expression but do not inhibit several other lytic activation pathways. Immunosuppressant drugs such as cyclosporine and tacrolimus but not rapamycin also inhibit BCR-mediated EBV activation. Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors.
Insights
B cell receptor (BCR) signaling activates Epstein-Barr virus (EBV) lytic replication. Drugs targeting BCR signaling, like ibrutinib, inhibit this activation in cell lines and patient B cells.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Epstein-Barr virus (EBV) establishes lifelong latency in B cells.
- B cell receptor (BCR) signaling is crucial for B cell function and can reactivate EBV.
- Understanding EBV reactivation pathways is key for managing EBV-associated diseases.
Purpose of the Study:
- To investigate the role of BCR signaling in EBV lytic induction.
- To evaluate the efficacy of BCR inhibitors and immunosuppressive drugs on EBV reactivation.
- To determine if BCR-mediated EBV activation occurs in primary patient B cells.
Main Methods:
- Utilized cell lines and primary peripheral blood mononuclear cells (PBBMCS).
- Administered drugs targeting BCR signaling (ibrutinib, idelalisib, dasatinib) and immunosuppressants (cyclosporine, tacrolimus, rapamycin).
- Assessed EBV lytic induction and BCR signaling pathways.
Main Results:
- BCR inhibitors (ibrutinib, idelalisib, dasatinib) effectively blocked BCR-mediated EBV lytic induction.
- Cyclosporine and tacrolimus inhibited BCR-mediated EBV reactivation, but rapamycin did not.
- mTORC2 signaling was found to contribute to BCR-mediated EBV lytic induction.
- BCR signaling activated EBV lytic induction in primary patient B cells, inhibited by ibrutinib and idelalisib.
Conclusions:
- BCR signaling is a critical pathway for EBV lytic induction.
- Clinically relevant BCR inhibitors can block EBV reactivation.
- Targeting BCR signaling offers a potential therapeutic strategy for EBV-associated conditions.
