A gammaherpesvirus Bcl-2 ortholog blocks B cell receptor-mediated apoptosis and promotes the survival of developing B cells in vivo.

Academic Article

Abstract

  • Gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) establish lifelong latency in their hosts and are associated with the development of several types of malignancies, including a subset of B cell lymphomas. These viruses are thought to co-opt the process of B cell differentiation to latently infect a fraction of circulating memory B cells, resulting in the establishment of a stable latency setpoint. However, little is known about how this infected memory B cell compartment is maintained throughout the life of the host. We have previously demonstrated that immature and transitional B cells are long-term latency reservoirs for murine gammaherpesvirus 68 (MHV68), suggesting that infection of developing B cells contributes to the maintenance of lifelong latency. During hematopoiesis, immature and transitional B cells are subject to B cell receptor (BCR)-mediated negative selection, which results in the clonal deletion of autoreactive B cells. Interestingly, numerous gammaherpesviruses encode homologs of the anti-apoptotic protein Bcl-2, suggesting that virus inhibition of apoptosis could subvert clonal deletion. To test this, we quantified latency establishment in mice inoculated with MHV68 vBcl-2 mutants. vBcl-2 mutant viruses displayed a marked decrease in the frequency of immature and transitional B cells harboring viral genome, but this attenuation could be rescued by increased host Bcl-2 expression. Conversely, vBcl-2 mutant virus latency in early B cells and mature B cells, which are not targets of negative selection, was remarkably similar to wild-type virus. Finally, in vivo depletion of developing B cells during chronic infection resulted in decreased mature B cell latency, demonstrating a key role for developing B cells in the maintenance of lifelong latency. Collectively, these findings support a model in which gammaherpesvirus latency in circulating mature B cells is sustained in part through the recurrent infection and vBcl-2-mediated survival of developing B cells.
  • Published In

  • PLoS Pathogens  Journal
  • Keywords

  • Animals, Apoptosis, B-Lymphocytes, Blotting, Western, Cell Differentiation, Cell Survival, Flow Cytometry, Gammaherpesvirinae, Herpesviridae Infections, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Polymerase Chain Reaction, Proto-Oncogene Proteins c-bcl-2, Receptors, Antigen, B-Cell, Tumor Virus Infections, Virus Latency
  • Digital Object Identifier (doi)

    Author List

  • Coleman CB; McGraw JE; Feldman ER; Roth AN; Keyes LR; Grau KR; Cochran SL; Waldschmidt TJ; Liang C; Forrest JC
  • Start Page

  • e1003916
  • Volume

  • 10
  • Issue

  • 2