Mouse model for acute Epstein–Barr virus infection

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-11, Vol.113 (48), p.13821-13826
• Main Authors: Wirtz, Tristan, Weber, Timm, Kracker, Sven, Sommermann, Thomas, Rajewsky, Klaus, Yasuda, Tomoharu
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - immunology; B-Lymphocytes - pathology; B-Lymphocytes - virology; Biological Sciences; CD40 Antigens - genetics; Cell Proliferation - genetics; Disease Models, Animal; Epstein-Barr virus; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - immunology; Epstein-Barr Virus Infections - pathology; Epstein-Barr Virus Infections - virology; Gene Expression Regulation, Viral; Germinal Center - immunology; Germinal Center - metabolism; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - pathogenicity; Humans; Immunology; Immunotherapy; Lymphoma; Mice; Perforin - deficiency; Perforin - genetics; Protein expression; Signal transduction; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - pathology; T-Lymphocytes - virology; Viral Matrix Proteins - biosynthesis; Viral Matrix Proteins - genetics; Virology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1616574113

Epstein–Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBV-infected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas. We have modeled acute EBV infection of naive and GC B cells in mice through timed expression of LMP1 and LMP2A. Although lethal when induced in all B cells, induction of LMP1 and LMP2A in just a small fraction of naive B cells initiated a phase of rapid B-cell expansion followed by a proliferative T-cell response, clearing the LMP-expressing B cells. Interfering with T-cell activity prevented clearance of LMP-expressing B cells. This was also true for perforin deficiency, which in the human causes a life-threatening EBV-related immunoproliferative syndrome. LMP expression in GC B cells impeded the GC reaction but, upon loss of T-cell surveillance, led to fatal B-cell expansion. Thus, timed expression of LMP1 together with LMP2A in subsets of mouse B cells allows one to study major clinically relevant features of human EBV infection in vivo, opening the way to new therapeutic approaches.