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Title: Epstein Barr Virus genome variation and functional analysis of the IR-1 internal repeat
Author: Correia, Samantha
ISNI:       0000 0004 7223 7410
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Epstein Barr Virus (EBV), a human gammaherpesvirus, establishes lifelong infection in B lymphocytes and is associated with a variety of malignancies including; Hodgkin's lymphoma, Burkitt's lymphoma and nasopharyngeal carcinoma. Due to the differences in geographical prevalence and expression patterns of EBV associated malignancies, it has been hypothesised that variation between EBV strains contributes to these malignancies. To investigate the natural variation of EBV strains, isolates were either collected or donated by contributors from a variety of sources; such as saliva, cell lines and tumour biopsies, which following DNA extraction and quantification, were Next-Generation sequenced. Analysis of saliva isolates determined that 50\% of isolates were co-infected with both type 1 and type 2 strains and, type 2 strains although most commonly found in Sub-Saharan Africa, were found to be the predominant strain within some British Caucasian individuals. Highly polymorphic proteins, EBNA-1 and LMP-1, were characterised into subtypes and following analysis, found to be both geographically and ethnically associated but not cancer associated. Certain EBNA-1 and LMP-1 subtypes were found to be linked and polymorphisms throughout the EBNA-1 protein were associated with specific 487 codons. Most of the EBV genome has been characterised but the complete function of the large internal repeat (IR-1), which typically consists of 5-8 copies of a 3 kilo base repeat unit, remains unclear. This repeat array is known to contain the latency promoter Wp, used initially during B cell infection, and the W1 and W2 exons which make up the repeat region of the EBNA-LP protein. Other components of the IR-1; the BWRF1 open reading frame and a 512bp inverted repeat both remain uncharacterised. Through the production of an inverted repeat knockout (ΔinvR) B95-8 EBV BAC, this study found that the inverted repeat is essential for B cell immortalisation and plays a role in virus production.
Supervisor: Farrell, Paul ; Allday, Martin Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral