Abstract
Epstein-Barr virus (EBV) is a ubiquitous herpesvirus infecting more than 90% of the adult population of the world. EBV is associated with a variety of diseases including infectious mononucleosis, lymphoproliferative diseases, malignancies such as Burkitt lymphoma and nasopharyngeal carcinoma, and autoimmune diseases including rheumatoid arthritis (RA). EBV in nature infects only humans, but in an experimental setting, a limited species of new-world monkeys can be infected with the virus. Small animal models, suitable for evaluation of novel therapeutics and vaccines, have not been available. Humanized mice, defined here as mice harboring functioning human immune system components, are easily infected with EBV that targets cells of the hematoimmune system. Furthermore, humanized mice can mount both cellular and humoral immune responses to EBV. Thus, many aspects of human EBV infection, including associated diseases (e.g., lymphoproliferative disease, hemophagocytic lymphohistiocytosis and erosive arthritis resembling RA), latent infection, and T-cell-mediated and humoral immune responses have been successfully reproduced in humanized mice. Here we summarize recent achievements in the field of humanized mouse models of EBV infection and show how they have been utilized to analyze EBV pathogenesis and normal and aberrant human immune responses to the virus.
Highlights
Murine viruses such as the mouse herpesvirus 68 (MHV-68) that is related to Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), and murine cytomegalovirus (CMV) homologous to human
These new-generation humanized mice can be infected with EBV [24,26,28,29,30,31], human immunodeficiency virus 1 (HIV-1) [32,33,34,35,36], human T-lymphotropic virus 1 (HTLV-1) [37,38,39], dengue virus [40,41], herpes simplex virus type 2 (HSV-2) [42], and Kaposi’s sarcoma-associated herpesvirus (KSHV) [43]
We focus on humanized mouse models of EBV infection, especially new-generation humanized mouse models, and describe how they have been utilized for the reproduction of key features of human EBV infection, including pathogenesis, immune responses, and latent infection
Summary
Mice have played a central role in biomedical researches including those on infectious diseases, as an accessible and versatile animal model. In one protocol (BLT (bone marrow, liver, thymus) mouse), tissues of human fetal liver and thymus, as well as HSC derived from the same liver were transplanted and enabled proper intrathymic selection of human T cells [26] These new-generation humanized mice can be infected with EBV [24,26,28,29,30,31], HIV-1 [32,33,34,35,36], HTLV-1 [37,38,39], dengue virus [40,41], herpes simplex. With a transgene encoding a fusion protein of the FK506 binding protein (FKBP) and caspase 8 hepatocytes,
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