Evasive strategies by the virus

In common with other persistent viruses, EBV has evolved strategies for evading immune responses so that it is never completely eliminated from the infected host. The hypotheses of EBV latency in healthy carriers have been greatly influenced by studies on EBV-positive BL tumors which are refractory to

CTL lysis. The primary mechanism of immune escape by these tumors is that expression of the immunodominant target antigens (EBNA3A, -3B and -3C) is repressed; EBNA1 is the only virallv-encoded protein expressed in BL tumors, and this protein has a unique strategy for evading CTL responses. EBNA1 contains a large glycinc/alanine-rich region that somehow prevents processing of EBNA1 target peptides for CTL recognition, but does not affect the ability of target peptides to be presented from other antigens in the same cell. In addition to the restricted pattern of viral gene expression, BL cells are also inherently impaired in endogenous antigen-presenting capability, owing to transcriptional downregulation of the TAP peptide transporter proteins and major histocompatibility complex (MHC) class I products. Finally, these tumors express low levels of cellular adhesion molecules that are involved in CTI.:target cell interactions.

It has long been thought that the immune-evasion strategies of BL may not be unique to the malignant cells, but might also be a feature of virus latency in normal healthy carriers. In certain respects this hypothesis is supported by recent research. Thus, in healthy carriers RT-PCR analysis of circulating lymphocytes suggests that EBNA1 and LMP2 are the only virally-encoded proteins expressed. The detection of LMP2 is unexpected, and does pose a problem as LMP2 is a membrane protein that can provide HLA-A2-binding peptides that are transported to HLA in the endoplasmic reticulum in a TAP-inde-pendent manner, and CTL recognition of TAP-nega-tive and LMP2-positive target cells has been demonstrated in vitro. However, there are several points that should be borne in mind. Firstly, the RT-PCR analysis does not reveal whether all the EBV-positive cells express LMP2, and neither does it indicate the level of expression. Secondly, LMP2 appears not to be an immunodominant target antigen for EBV-spe-cific CTL. Thirdly, it may be relevant the latent F.BV-carrying cells in vivo lack expression of the CD80 costimulatory molecule.

Given the potent transforming capacity of EBV, it is very important that strategies for immune evasion are balanced by mechanisms for eliminating excessive lymphoproliferation. In this respect it is notable that the LMP1 gene, whose expression is essential for EBV-induced growth transformation of resting B cells, has a major effect upon the immunogenicity of the target cell by upregulating TAP, HLA and cell surface accessory molecules. This ensures that EBV-induced proliferation of normal B cells is accompanied by a concomitant sensitization to cellular immune responses.

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