Dalton-Griffin, L.; (2010) The role of host cell factors in the lytic reactivation of Kaposi’s sarcoma-associated herpesvirus from latency. Doctoral thesis , UCL (University College London).

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Abstract

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.

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