title: A gammaherpesvirus Bcl-2 ortholog blocks B cell receptor-mediated apoptosis and promotes the survival of developing B cells in vivo.
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.
authors: Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Carrie B
authors: CB
authors: Coleman
authors: Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Jennifer E
authors: JE
authors: McGraw
authors: Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Emily R
authors: ER
authors: Feldman
authors: Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Alexa N
authors: AN
authors: Roth
authors: Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Lisa R
authors: LR
authors: Keyes
authors: Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Katrina R
authors: KR
authors: Grau
authors: Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Stephanie L
authors: SL
authors: Cochran
authors: Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors: Thomas J
authors: TJ
authors: Waldschmidt
authors: Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Chengyu
authors: C
authors: Liang
authors: Department of Microbiology & Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors: J Craig
authors: JC
authors: Forrest
authors: Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors: Scott A
authors: SA
authors: Tibbetts
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000821:virology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D005434:Flow Cytometry; D018142:Gammaherpesvirinae / Q000502:physiology*; D006566:Herpesviridae Infections / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D014412:Tumor Virus Infections / Q000276:immunology*; D017735:Virus Latency / Q000276:immunology*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell