Epstein-Barr virus infection in humans: from harmless to life endangering virus-lymphocyte interactions.

After the primary infection, that may or may not cause infectious mononucleosis, the ubiquitous Epstein-Barr virus (EBV) is carried for lifetime. The great majority of adult humans are virus carriers. EBV was discovered in a B-cell lymphoma (Burkitt lymphoma). EBV infection in humans is the example for the power of immune surveillance against virus transformed, potentially malignant cells. Although the virus can transform B lymphocytes in vitro into proliferating lines, it induces malignancy directly only in immunosuppressed hosts. EBV-induced growth transformation occurs only in B lymphocytes. It is the result of a complex interaction between virally encoded and cellular proteins. Different forms of the virus-cell and the cell-host interactions have evolved during a long period of coexistence between the virus and all Old World (but not New World) primates. The asymptomatic carrier state is based on a viral-strategy that downregulates the expression of the transforming proteins in the virus-carrying cell. In addition to the silent viral-gene carriers and the expressors of the nine virus-encoded genes that drive the growth program, virus carrying cells exist that show other patterns of gene expression, depending on the differentiated state of the host cell. Certain combinations contribute to malignant transformation, but only in conjunction with additional cellular changes. These are induced by direct or cytokine-mediated interactions with normal cells of the immune system.

Pathogenesis of Epstein-Barr virus (EBV)-carrying lymphomas.

The EBV carrier state is almost general in men. The virus induces B lymphocyte proliferation in vitro, but this is counteracted in vivo by the immune response. Therefore, EBV-induced malignancies occur only when the immune response is impaired, e.g. in transplant recipients. The versatility of the viral gene expression strategy secures the consistent maintainance of the virus in healthy individuals. The viral proteins required for transformation render the cell immunogenic. Expression of the transforming genes leads to rejection, but these genes are not required for the maintenance of the viral genome. EBV is an important contributor for malignant transformation, even when it does not directly induce cell proliferation. Several mechanisms have been unravelled in EBV-associated tumors whereby the virus may modify the cellular phenotype and may influence the interaction of tumor cells with their microenvironment. The virus carrier state can lead to the evasion of apoptosis and can intensify the response to growth promoting signals, too.

Wild-type p53 activates SAP expression in lymphoid cells.

SAP is an adaptor molecule with one SH2 domain and it is expressed in activated T and NK cells, where it is required for the appropriate signaling from the SLAM family of surface receptors. Deleted or mutated SAP genes that encode functionally defective protein are associated with the X-linked lymphoproliferative disease (XLP). This primary immunodeficiency is characterized by extreme sensitivity to Epstein-Barr virus (EBV) infection, dysgammaglobulinemia and a high rate of lymphoma development. The vigorous T- and B-cell proliferation that follows EBV infection and the high incidence of lymphomas (30%) in XLP patients might reflect functional defects in cell cycle and/ or apoptosis control. Our experiments show that SAP is a target of p53. In Burkitt lymphoma (BL) lines transfected with a temperatur-sensitive (ts) p53, SAP mRNA and protein expression was dependent on wild-type (wt) p53. Activation of endogenous wt p53 in BLs and lymphoblastoid cell lines led to the induction of SAP and this was inhibited by the specific p53 inhibitor pifithrin-alpha. Cell lines that carried mutant p53 did not express SAP under similar conditions. Moreover, we have shown binding of wt p53 to the promoter region of SAP by ChIP assay. Our results suggest that SAP contributes to the execution of some p53 functions.