Epstein-Barr Virus (EBV) is a human gamma herpesvirus that infects about 95% of world population. The life cycle of EBV can be divided into two stages: latent and lytic. During latency, the virus DNA is maintained as a nuclear episome with minimal protein expression to avoid immune recognition. Although primary EBV infection in childhood is usually asymptomatic, infection with EBV is associated with a wide range of proliferative diseases such as post-transplant lymphoproliferative disease (PTLD), Burkitt’s lymphoma (BL) and primary effusion lymphoma (PEL). Despite EBV infection being common, less is understood about the host control of the lytic virus life cycle or the sequence diversity of the viral genome. This thesis investigates the reactivation of lytic EBV replication in both PEL and BL cell lines and whole genome EBV sequence diversity. X-box binding protein 1 (XBP-1), a transcriptional activator that is essential for plasma cell differentiation, reactivates Kaposi sarcoma herpesvirus (KSHV), a closely related gamma herpesvirus from latency. With KSHV and EBV co-infection in PEL, the possibility of XBP-1 also reactivating EBV is investigated here. We show XBP-1 does not induce EBV into the lytic cycle in tumour B-cell backgrounds, either with or without protein kinase D. This contrasts previous observations. The lytic replication of EBV generates sequence diversity. To further understand EBV genomes and their association with the malignancies, a pipeline for sequencing EBV whole genomes using Next Generation Sequencing (NGS) has been developed. EBV whole genomes from mature Bcell tumour lines, such as PEL and BL have been sequenced assembled along with EBV from blood samples of PTLD patients. Examining the EBV whole genome sequences from PTLD blood samples through time suggests dynamic EBV sequence evolution can be observed in vivo. We conclude that EBV genomes contain higher variation than previously expected, and further study is needed to understand the relationship between EBV and the diseases.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:625912 |
| Date | January 2012 |
| Creators | Lai, Y. I. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1362852/ |
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