Mouse model for acute Epstein–Barr virus infection

Abstract

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. EBVinfected 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 LMPexpressing 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.pstein-Barr Virus (EBV) is a γ-herpes virus that infects human B cells and growth-transforms them in vitro. Infection is usually asymptomatic, but can lead to infectious mononucleosis (IM) in teenagers and adults (1). EBV drives infected B cells into proliferation, but the symptoms of IM, mainly fever, lymphadenopathy, and splenomegaly, are believed to result from the subsequent activation and massive proliferation of EBV-reactive T cells (2). After the acute phase of infection, EBV persists in a small subset of memory B cells throughout life and is kept in check by memory T cells (2-4). Although an EBV infection is harmless to most people, immunocompromised individuals can develop severe complications. Genetic defects that lead to impaired T-cell function predispose to EBV-driven lymphoproliferative diseases, such as familial hemophagocytic lymphohistiocytosis (FHL) (5, 6). FHL presents in infants and is characterized by persistent fever, hemophagocytosis, and cytokine storms. These symptoms are attributed to proliferation and cytokine production by macrophages and T cells (5-7). About onethird of FHL cases are caused by mutations in the PRF1 gene encoding perforin (8). EBV is also highly associated with HIV-related and posttransplantation lymphomas, which are usually derived from germinal center (GC) B cells. Most likely EBV is the causative agent for these lymphomas, transforming GC B cells when T-cell immunosurveillance is impeded owing to HIV infection or immunosuppressive therapy after organ transplantation (1, 9, 10).The activation and proliferation of EBV-infect...

Mouse model of Epstein–Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease

“…GC B-cell LMP1 and LMP2A expression was necessary for induction of fatal lymphoproliferative disease in our model. This result is in agreement with prior LMP2A models, where transgenic LMP2A expression from an early stage in B-cell development alone or together with LMP1 (12,31,32), or alone in GC B cells (19). Interestingly, we did not observe disease in LMP1 AID T/NK-cell-deficient mice over a 14-d interval.…”

“…Our results, together with the results of another recent mouse model of GC LMP1/2A coexpression (32), build on the observations that LMP2A augments LMP1 signaling (36,37) and that LMP1/2A synergistically accelerate carcinogenesis (38). CD19 promoter-driven LMP1/2A coexpression from early in B-cell development, but not CD19-driven expression of LMP1 or LMP2A alone, causes fatal neonatal lymphoproliferative disease (32).…”

Epstein-Barr Virus LMP1-Mediated Oncogenicity

“…EBV latency II is observed in Hodgkin lymphoma (HL) and also in NPC. GC B-cell LMP1 and LMP2A coexpression causes rapidly fatal lymphoproliferative disease in T-cell deficient mice (68), further highlighting the key role of immune surveillance in countering LMP1 oncogenicity. NK cells also have key host defense roles necessary for host defense against EBV, and combined T/NK-cell depletion results in massive LMP1/ LMP2A-driven GC B-cell outgrowth, plasmablast differentiation, and death within 12 days (69).…”

Oncogene-specific T cells fail to eradicate lymphoma-initiating B cells in mice

“…3 In mouse models transgenic for Epstein-Barr virus antigens LMP1 and LMP2, lymphoproliferative disease is also controlled by T cells. 34,35,38 These antigens are unique because they have profound effects on the B-cell phenotype and mimic activation signals, which likely explains elimination of "activated" B cells by T cells, not necessarily LMP specific. We do not have any indication that TAg affects B-cell activation.…”

“…[28][29][30][31][32][33][34] Some of these studies demonstrated control of lymphoma development by natural killer cells, T cells, or T-cell mediators. [33][34][35][36][37][38][39] These models have given important insights into disease development but have 3 drawbacks: (1) they do not recapitulate the sporadic nature of nonviral B-cell lymphomas, (2) no antigen is known for which the mice are not yet tolerant at birth, and/or (3) no T-cell epitope is known to study specific T-cell responses.…”