The role of host cell factors in the lytic reactivation of Kaposi's sarcoma-associated herpesvirus from latency

Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) has two stages to its life \ncycle; latency and lytic replication. KSHV latent infection is associated with the \nB-cell tumour, Primary Effusion Lymphoma (PEL). During latency the viral \nepisome is maintained, few viral genes are expressed and no infectious virions \nare produced. The switch between phases is controlled by the viral transcription \nfactor, RTA encoded by ORF50. Lytic replication, which results in the \nproduction of progeny virions, can be triggered by a variety of causes \nsuggesting KSHV has the ability to reactivate in response to a multitude of \nscenarios. However, many of the stimuli described, to date, have no clear \nphysiological relevance. \nThis thesis investigates how cellular transcription factors can induce the KSHV \nlytic cycle. Firstly, a model system for monitoring KSHV lytic replication is \ndeveloped and characterised. This system is then employed to demonstrate \nhow the cellular transcription factor XBP-1s is able to induce KSHV reactivation. \nXBP-1 is responsible for the terminal differentiation of B-cells into plasma cells \n(PCs) and is a major regulator of the unfolded protein response (UPR). PEL do \nnot express the transcription factor X-box binding protein-1 (XBP-1). When \nspliced active XBP-1s is supplied, PEL cells differentiate towards a PC and \ninduce KSHV lytic replication. B-cell terminal differentiation is therefore a \nphysiological trigger of KSHV lytic reactivation. To understand the role of host \ncell factors in this interaction further, the gene expression changes that occur \nwhen XBP-1s is supplied to PEL are also examined. Finally, we investigate the \nspecific roles of XBP-1s and HIF-1α in the KSHV reactivation seen in response \nto hypoxia. We conclude that both B-cell differentiation and hypoxia are \nphysiologically relevant triggers for KSHV lytic cycle induction, highlighting \nsome of the many complex interactions between the virus and its host.