Fox, Christopher Paul (2011)
Ph.D. thesis, University of Birmingham.
Epstein-Barr virus (EBV) is strongly associated with rare but aggressive lymphoproliferative diseases of NK and T cell origin. The finding of clonal and episomal forms of the virus in tumour cells from these clinically diverse diseases indicates involvement of EBV at an early stage of lymphomagenesis. However, many fundamental questions about EBV’s contribution to pathogenesis remain unanswered. In vivo analyses herein found that infection of tonsillar (but not peripheral blood) T cells occasionally occurred in primary and persistent infection, whilst infection of NK cells was a rare event. By contrast, a high EBV load was found in peripheral blood NK cells from 3 adult patients with EBV-associated haemophagocytic-lymphohistiocytosis, a disease previously associated with CD8+ T cell infection in children.
Complementary studies examined EBV latent gene expression in EBV+ T/NK malignancies. Notwithstanding an apparent absence of latent membrane protein 2A and 2B (LMP2A/B), these tumour cells were recognised and killed by LMP2-specific cytotoxic T lymphocytes. This paradox was resolved by identifying a novel LMP2 mRNA, initiated from within the terminal repeat (TR) region of the viral genome and containing downstream epitope-encoding exons. Expression of LMP2-TR in T/NK cell lines and primary tissue implicates this truncated viral protein in T/NK lymphomagenesis.
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