Epstein-Barr virus infection and human malignancies

Abstract

The Epstein-Barr virus (EBV) is a herpes virus which establishes a life-long persistent infection in over 90% of the human adult population world-wide. Based on its association with a variety of lymphoid and epithelial malignancies, EBV has been classified as a group 1 carcinogen by the International Agency for Research on Cancer. In this article we discuss the evidence supporting an aetiological role for EBV in the pathogenesis of human tumours. The biology of EBV infection will be described with special emphasis on viral transforming gene products. A brief survey of EBV-associated tumours is followed by a discussion of specific problems. Evidence is presented which suggests that failures of the EBV-specific immunity may play a role in the pathogenesis of EBV-associated tumours also in patients without clinically manifest immunodeficiencies. Finally, the timing of EBV infection in the pathogenesis of virus-associated malignancies is discussed. There is good evidence that EBV infection precedes expansion of the malignant cell populations in some virus-associated tumours. However, this is clearly not always the case and for some of these tumours there are indications that clonal genetic alterations may occur prior to EBV infection. Thus, whilst there is good evidence to suggest that EBV is a human carcinogen, its precise role(s) in the development of virus-associated human tumours requires clarification.

Figure 1

In situ hybridization with ³⁵S-labelled EBER-specific probes reveals numerous EBV-infected cells in a tonsil from a patient with acute infectious mononucleosis (a, black grains). Immunohistochemical analysis of a tonsil from an infectious mononucleosis patient reveals expression of EBNA2 (b, red labelling) and of LMP1 (c, red labelling; note a LMP1-positive Reed-Sternberg-like cell, arrow) in many cells. Only rare EBV-positive cells are detectable in a tonsil from a chronic virus carrier (d, black grains). EBER-specific in situ hybridization of a case of Hodgkin's disease using nonradioactive probes reveals the presence of the virus in Hodgkin and Reed-Sternberg cells (e, red labelling; note isolated EBV-positive small reactive lymphocytes, arrow). EBV-positive Hodgkin and Reed-Sternberg cells also express LMP1 (f, red labelling). EBV is detected in the neoplastic cells of an undifferentiated nasopharyngeal carcinoma using nonradioactive EBER-specific in situ hybridization (g, red labelling). In the same case, the tumour cells also express LMP1 (h, red labelling).