Heath, Emily (2011)
Ph.D. thesis, University of Birmingham.
EBV is a lymphotropic herpesvirus that establishes lifelong persistence in the memory B cell compartment of the human host. It is still unclear, however, whether the virus infects memory B cells directly, or first targets naive B cells, driving them to differentiate into memory B cells via germinal centre (GC) transit. Using ex vivo analysis of sorted B cell subsets, we have found that whilst EBV preferentially colonises isotype-switched memory B cells, the virus was excluded from tonsillar GC B cells. Furthermore we found substantial viral loads in non-switched memory B cell populations, whose origins are likely to be germinal centre-independent. Using in vitro infection experiments, we showed that enzymes AID, UNG and pol-η, which are associated with the GC processes somatic hypermutation (SHM) and class switch recombination (CSR) were upregulated in EBV-infected B cells. Indeed following in vitro transformation, SHM of immunoglobulin (Ig) genes was induced in a proportion naive B cells. Whilst these cells did not undergo CSR following EBV infection alone, additional cytokine stimulation together with CD40L was able to induce isotype switching. EBV infection in vitro together with the provision of appropriate signals was therefore able to induce genotypic and phenotypic memory B cell characteristics in naive B cells, in a non-GC environment. Taken together our findings suggest that GC transit is not an essential requirement for EBV colonisation of the memory B cell population.
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