Epstein-Barr Virus-Infected B Cells Expanding in Germinal Centers of Infectious Mononucleosis Patients Do Not Participate in the Germinal Center Reaction

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-04, Vol.100 (8), p.4730-4735
• Main Authors: Kurth, Julia, Hansmann, Martin-Leo, Rajewsky, Klaus, Küppers, Ralf
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; B lymphocytes; B-Lymphocytes - immunology; B-Lymphocytes - pathology; B-Lymphocytes - virology; Base Sequence; Biological Sciences; Cell lines; Cells; DNA, Viral - genetics; DNA, Viral - isolation & purification; Epstein Barr virus infections; Epstein-Barr virus; Gene Expression; Genes; Genes, Viral; Germinal Center - immunology; Germinal Center - pathology; Germinal Center - virology; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - immunology; Herpesvirus 4, Human - pathogenicity; Humans; Immunology; Infections; Infectious Mononucleosis - immunology; Infectious Mononucleosis - pathology; Infectious Mononucleosis - virology; Lymphoid tissue; Lymphoma; Lymphoma, B-Cell - etiology; Male; Molecular Sequence Data; Palatine tonsils; Polymerase chain reaction; T lymphocytes; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2627966100

To assess the impact of the germinal center (GC) reaction on viral spread in Epstein-Barr virus (EBV) infection, we isolated EBV+GC B cells from the tonsils of two infectious mononucleosis patients, sequenced their rearranged V genes, and determined expression of the EBV latency genes EBV nuclear antigen 2 and latent membrane protein 1. Most EBV+GC B cells belonged to clones of cells harboring somatically mutated V gene rearrangements. Ongoing somatic hypermutation, the hallmark of the GC reaction, was seen only in uninfected GC B cell clones, not in EBV+B cell clones. Thus, in infectious mononucleosis, GC and/or memory B cells are directly infected by EBV and expand without somatic hypermutation, whereas the GC passage of EBV-infected naive B cells does not contribute detectably to the generation of infected memory B cells, the main reservoir of EBV during persistence. Most, if not all, EBV-infected cells in GCs exhibited an unusual EBV gene expression pattern in that they were positive for EBV nuclear antigen 2 but negative for latent membrane protein 1. Although the three main types of EBV-associated B cell lymphomas (Burkitt's, Hodgkin's, and posttransplant lymphomas) presumably are derived from GC B cells, EBV+GC B cells resembling these EBV+GC B cell lymphomas in terms of EBV gene expression and somatic hypermutation pattern could not be identified.