The intersection of Epstein-Barr virus with the germinal center.
The current model of Epstein-Barr virus (EBV) infection and persistence in vivo proposes that EBV uses the germinal center (the GC model) to establish a quiescent latent infection in otherwise-normal memory B cells. However, the evidence linking EBV-infected cells and the GC is only indirect and limited. Therefore, a key portion of the model, that EBV-infected cells physically reside and participate in GCs, has yet to be verified. Furthermore, recent experiments suggested that upon infection of GC cells the viral growth latency transcription program is dominant and GC functionality and phenotype are ablated, i.e., EBV infection is not consistent with GC function. In this study we show that in vivo, EBV-infected B cells in the tonsils retain expression of functional and phenotypic markers of GC cells, including bcl-6 and AID. Furthermore, these cells are physically located in the GC and express a restricted form of latency, the default latency program. Thus, the EBV default latency transcription program, unlike the growth latency program, is consistent with the retention of GC functionality in vivo. This work verifies key components of the GC model of EBV persistence and suggests that EBV and the GC can interact to produce the latently infected memory cells found in the periphery. Furthermore, it identifies latently infected GC B cells as a potential pathogenic nexus for the development of the EBV-positive, GC-associated lymphomas Hodgkin's disease and Burkitt's lymphoma.
Roughan
Jill E
JE
Department of Pathology, Jaharis Building, Tufts University School of Medicine, 150 Harrison Ave., Boston, MA 02111, USA.
Thorley-Lawson
David A
DA
D000293:Adolescent; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000821:virology*; D003564:Cytidine Deaminase / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D018858:Germinal Center / Q000276:immunology / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000254:growth & development* / Q000502:physiology; D006801:Humans; D014066:Palatine Tonsil / Q000276:immunology / Q000821:virology*; D051560:Proto-Oncogene Proteins c-bcl-6; D017735:Virus Latency; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase