KSHV manipulation of the B-cell differentiation programme to establish lytic and latent viral replication. (360G-Wellcome-079412_Z_06_Z)

The human gamma herpesviruses, Kaposi s sarcoma associated herpesvirus (KSHV) and Epstein Barr Virus (EBV) maintain their latent life cycle in B-cells. Infectious virus is produced by lytic reactivation from latency to allow onward virus transmission despite a functioning immune system. To do this EBV is proposed to usurp B-cell developmental programmes and functional gene networks. We hypothesis KSHV adopts a similar strategy. When errors occur in this B-cell manipulation lymphoproliferations and lymphomas develop. We have shown that KSHV Primary Effusion Lymphoma (PEL) is a tumour of mature B cell plasmablasts that are blocked at the final stage of B-cell differentiation into plasma cells by a non-activated XBP-1 pathway. When XBP-1 is supplied to PEL, terminal PC differentiation occurs and KSHV lytic cycle is induced. This project will determine the mechanistic differences in gene expression programmes between PEL and the normal cellular counterparts, plasmablasts and plasma cel ls. To interpret these integrated gene expression programmes we will produce computational systems models of mature B-cell transcription factor networks to identify additional B-cell processes that KSHV proteins manipulate. Exemplifying this strategy we will investigate the role of XBP-1 in the induction of KSHV lytic replication and PEL terminal differentiation to plasma cells.