A new model of Epstein-Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas.
Epstein-Barr virus (EBV) infects cells in latent or lytic forms, but the role of lytic infection in EBV-induced lymphomas is unclear. Here, we have used a new humanized mouse model, in which both human fetal CD34(+) hematopoietic stem cells and thymus/liver tissue are transplanted, to compare EBV pathogenesis and lymphoma formation following infection with a lytic replication-defective BZLF1-deleted (Z-KO) virus or a lytically active BZLF1(+) control. Both the control and Z-KO viruses established long-term viral latency in all infected animals. The infection appeared well controlled in some animals, but others eventually developed CD20(+) diffuse large B cell lymphomas (DLBCL). Animals infected with the control virus developed tumors more frequently than Z-KO virus-infected animals. Specific immune responses against EBV-infected B cells were generated in mice infected with either the control virus or the Z-KO virus. In both cases, forms of viral latency (type I and type IIB) were observed that are less immunogenic than the highly transforming form (type III) commonly found in tumors of immunocompromised hosts, suggesting that immune pressure contributed to the outcome of the infection. These results point to an important role for lytic EBV infection in the development of B cell lymphomas in the context of an active host immune response.
Ma
Shi-Dong
SD
University of Wisconsin, Department of Oncology, McArdle Laboratory, University of Wisconsin, Madison, WI 53706, USA.
Hegde
Subramanya
S
Young
Ken H
KH
Sullivan
Ruth
R
Rajesh
Deepika
D
Zhou
Ying
Y
Jankowska-Gan
Ewa
E
Burlingham
William J
WJ
Sun
Xiaoping
X
Gulley
Margaret L
ML
Tang
Weihua
W
Gumperz
Jenny E
JE
Kenney
Shannon C
SC
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D016031:Liver Transplantation; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000637:transplantation; D015534:Trans-Activators / Q000235:genetics; D014183:Transplantation, Heterologous; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency
D018952:Antigens, CD34; C063676:BZLF1 protein, Herpesvirus 4, Human; D015534:Trans-Activators; D014764:Viral Proteins