Deciphering the role of Epstein-Barr virus in the pathogenesis of T and NK cell lymphoproliferations

Abstract

Epstein-Barr virus (EBV) is a highly successful herpesvirus, colonizing more than 90% of the adult human population worldwide, although it is also associated with various malignant diseases. Primary infection is usually clinically silent, and subsequent establishment of latency in the memory B lymphocyte compartment allows persistence of the virus in the infected host for life. EBV is so markedly B-lymphotropic when exposed to human lymphocytes in vitro that the association of EBV with rare but distinct types of T and NK cell lymphoproliferations was quite unexpected. Whilst relatively rare, these EBV-associated T and NK lymphoproliferations can be therapeutically challenging and prognosis for the majority of patients is dismal. In this review, we summarize the current knowledge on the role of EBV in the pathogenesis of these tumours, and the implications for treatment.

Figure 1

Haemophagocytosis in the bone marrow. A photomicrograph of a bone marrow aspirate (original magnification x200) from a UK patient, showing an area of marked macrophage activity and haemophagocytosis. Lipid-laden macrophages are seen to engulf haemopoeitic precursors.

Figure 2

Patterns of latent viral gene expression in EBV-associated tumours. Schematic illustrating major patterns of EBV gene expression observed in different virus:host interactions; non-coding RNAs and micro-RNAs are indicated in green type, nuclear proteins in black type, and membrane proteins in blue type. Latency 0, sometimes referred to as 'in vivo latency, is the type of latency observed in non-dividing circulating memory B cells of healthy carriers; it is possible that the majority of these cells express no viral genes at all, but that a minority may express non-coding RNAs. Latency I was originally identified in Burkitt' lymphoma, Latency II in nasopharyngeal carcinoma and Hodgkin's lymphoma, and Latency III in post-transplant lymphoproliferative disease.

Figure 3

Heterogeneous LMP1 expression within an ENKTL tumour. Upper photomicrograph: EBER in-situ hybridisation on a 4 μm formalin-fixed, paraffin-embedded ENKTL tissue section (optical magnification x200). Courtesy of Dr Simon O'Connor, Department of Histopathology, Nottingham University Hospitals. Lower photomicrograph: Immunohistochemical stain of a 4 μm formalin-fixed, paraffin-embedded ENKTL tissue section using CS1-4 (anti-LMP1) antibodies. The image was captured with a Nikon CoolpixE995 digital camera, via a Nikon Eclipse E400 microscope (optical magnification, ×400).