The role of Epstein-Barr virus in neoplastic transformation.
In this review, we focus on new data from basic, translational and clinical research relating to the Epstein-Barr virus (EBV). Beside its well-known tropism for B lymphocytes and epithelial cells, EBV also infects T lymphocytes, monocytes and granulocytes. After primary infection, EBV persists throughout the life span in resting memory B cells, from where it is reactivated upon breakdown of cellular immunity. In the process of neoplastic transformation, the EBV-encoded latent membrane protein 1 (LMP1) oncogene represents the major driving force. LMP1 acts like a constitutively activated receptor of the tumor necrosis factor receptor family and allows the amplification or bypassing of physiological regulatory signals through direct and indirect interactions with proteins of the tumor necrosis factor receptor-associated factor (TRAF) family. TRAF2-mediated NF-kappaB activation, AP-1 induction and JAK3/STAT activation may result in sustained proliferation leading to lymphoma. The ability of LMP1 to suppress germinal center formation and its capacity to mediate its own transcriptional activation shed new light on the pathogenesis of EBV-associated latency type II lymphoproliferations like Hodgkin's disease and angioimmunoblastic lymphadenopathy. The carboxy terminus of LMP1 is also a reliable marker for individual EBV strain identification and thus offers new possibilities in tracing the molecular events leading to posttransplant lymphoproliferative disorders (PTLDs). Cytotoxic T lymphocytes directed against well-characterized epitopes of EBV latency genes represent an already successful and promising therapeutic approach to EBV-associated lymphomas, in particular PTLDs.
Knecht
H
H
Institute for Clinical Research, Swiss Paraplegic Centre, Nottwil, Switzerland. hans.knecht@paranet.ch
Berger
C
C
Rothenberger
S
S
Odermatt
B F
BF
Brousset
P
P
D017209:Apoptosis; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000821:virology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D011506:Proteins / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2; D014763:Viral Matrix Proteins / Q000502:physiology*
D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D014763:Viral Matrix Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases