Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) has two stages to its life
cycle; latency and lytic replication. KSHV latent infection is associated with the
B-cell tumour, Primary Effusion Lymphoma (PEL). During latency the viral
episome is maintained, few viral genes are expressed and no infectious virions
are produced. The switch between phases is controlled by the viral transcription
factor, RTA encoded by ORF50. Lytic replication, which results in the
production of progeny virions, can be triggered by a variety of causes
suggesting KSHV has the ability to reactivate in response to a multitude of
scenarios. However, many of the stimuli described, to date, have no clear
physiological relevance.
This thesis investigates how cellular transcription factors can induce the KSHV
lytic cycle. Firstly, a model system for monitoring KSHV lytic replication is
developed and characterised. This system is then employed to demonstrate
how the cellular transcription factor XBP-1s is able to induce KSHV reactivation.
XBP-1 is responsible for the terminal differentiation of B-cells into plasma cells
(PCs) and is a major regulator of the unfolded protein response (UPR). PEL do
not express the transcription factor X-box binding protein-1 (XBP-1). When
spliced active XBP-1s is supplied, PEL cells differentiate towards a PC and
induce KSHV lytic replication. B-cell terminal differentiation is therefore a
physiological trigger of KSHV lytic reactivation. To understand the role of host
cell factors in this interaction further, the gene expression changes that occur
when XBP-1s is supplied to PEL are also examined. Finally, we investigate the
specific roles of XBP-1s and HIF-1α in the KSHV reactivation seen in response
to hypoxia. We conclude that both B-cell differentiation and hypoxia are
physiologically relevant triggers for KSHV lytic cycle induction, highlighting
some of the many complex interactions between the virus and its host