Background

The evolution of the complex interaction between man and EBV originated with the primate ancestors. During the long history of the coexistence it evolved to be largely harmless, that is mainly determined by the variability of viral gene expression

Department of Microbiology, Tumor and Cell Biology (MTC) Karolinska Institutet, Stockholm, 17177, Sweden

E. Yefenof (ed.), Innate and Adaptive Immunity in the Tumor Microenvironment. © Springer 2008

regulated by the differentiation of the host cell. Today, man and all Old, but not New World, primates harbor EBV-like viruses [1]. After the primary infection humans become virus carriers for lifetime and develop immunity against the virally encoded antigens. The maintenance of the virus in face of the immune response is secured by viral programs in which the immunogenic viral proteins are not expressed.

EBV shows a high degree of B-cell tropism. It binds to a B lymphocyte-specific surface molecule, CD21 (receptor for the C3d fragment of complement). Binding of the viral envelop to the receptor induces cell activation. The infected cells can enter into the mitotic cycle and maintain proliferating capacity [1-3]. The EBV generated B-cell lines are referred to as lymphob-lastoid cell lines (LCL). In these cells the viral genome is maintained in epi-somal form and expresses nine proteins. The growth transformation is accompanied by phenotypic changes in the cells, including the expression of co-stimulatory cell surface molecules that are pivotal for their recognition by the immune system. Consequently, unless their immune response is compromised, healthy individuals are saved from the emergence of EBV-induced malignancies.

The harmless maintenance of this transforming virus in humans is ensured on one hand by the modulation of the viral gene expression, allowing maintenance of the viral genome in B-cells without imposition of immunogenicity; on the other hand by the strong immunogenicity of the cells that express the growth promoting EBV-encoded proteins and are therefore eliminated [4].

Primary infection occurs usually in adolescents. In about half of the individuals it is followed by infectious mononucleosis (IM), a benign disease with highly variable severity and symptoms. The symptoms reflect the presence of activated B-cells and the developing immune response.

Infection of B-cells in vitro has revealed the molecular details of the complexity of virus-host cell interaction and the immunological recognition of the latently infected B-cells. In contrast to B lymphocytes, infection of epithelial-, T-, and NK-cells in vitro can be achieved only through manipulation of the virus or the host cell, such as using virus constructs with introduced selection markers and target cells with inserted viral receptors. However, the development of sensitive assays has led to the discovery of EBV-positive malignancies originating in T and NK lymphocytes, epithelial and mesenchymal cells indicating that these cell lineages are occasionally infected in vivo.

The EBV-harboring malignant B-cell lymphomas differ considerably from the non-B malignancies. The resident viral genome can induce proliferation autonomously only in the former, while additional factors, among them ones contributed by the microenvironment, contribute to the latter.

For the discussion of the role of EBV in the pathogenesis of the various lymphomas and of the contribution of the microenvironment it is necessary to consider the various strategies of EBV gene expression and their impact on the target cell.

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