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An Analysis of Human Cytomegalovirus Gene Family Function

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An Analysis of Human Cytomegalovirus Gene Family Function An Analysis of Human Cytomegalovirus Gene Family Function A thesis submitted in candidature for the degree of DOCTOR OF PHILOSOPHY by Hester Amy Nichols September 2018 Division of Infection and Immunity, School of Medicine, Cardiff University Declarations This work has not been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed…......................................................... (candidate) Date................................ STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD Signed…......................................................... (candidate) Date................................ STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated, and the thesis has not been edited by a third party beyond what is permitted by Cardiff University’s Policy on the Use of Third Party Editors by Research Degree Students. Other sources are acknowledged by explicit references. The views expressed are my own. Signed…......................................................... (candidate) Date................................ STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available online in the University’s Open Access repository and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed…......................................................... (candidate) Date................................ STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available online in the University’s Open Access repository and for inter-library loans after expiry of a bar on access previously approved by the Academic Standards & Quality Committee. Signed…......................................................... (candidate) Date................................ i Acknowledgements I would firstly like to express my gratitude to my supervisors, Dr Ceri Fielding and Prof. Gavin Wilkinson for giving me the opportunity to do a PhD, and for their support, guidance, valued insights and patience throughout, alongside their support of me attending conferences to further my professional and personal development. I would also like to thank my supervisor Dr Peter Tomasec who sadly passed away last year. I am also grateful to Dawn Roberts for her technical support, and would like to thank everyone within the Wilkinson lab, for their help in the lab and their valuable input within team meetings. I would especially like to thank everyone in the lab and the PhD students in the building for their friendship over the last 3 years, and for making the lab such an enjoyable workplace. I would especially like to thank Simone Forbes for her constant enthusiasm and encouragement throughout my writing up period; and Carmen Bedford who I was lucky enough to meet at the start of my Cardiff adventure and continue my PhD journey with, and who has kept me sane with multiple cups of tea and chick flicks over the years. I would also like to thank my funding body, the Medical Research Council (MRC), and our collaborators in Glasgow (in the laboratory of Dr Andrew Davison, MRC-University of Glasgow Centre for Virus Research) and in Cambridge (in the laboratory of Dr Paul Lehner, Cambridge Institute for Medical Research) for their help with my project. Finally, I would like to thank my boyfriend Jason Vincent and my family, especially my mum, dad and sister, for supporting me and believing in me throughout my PhD studies. I couldn’t have gotten through it without you all! ii Summary Human cytomegalovirus (HCMV) is a β-herpesvirus that causes complications in immuno- compromised individuals and is the leading infectious cause of birth defects. The HCMV genome contains 15 gene families, which contain between 2 to 14 members. One of these, the US12 gene family, consists of a sequential cluster of 10 genes (US12 to US21) that are highly conserved in clinical isolates. This family has roles in tropism and immune evasion and was recently found to regulate the cell surface expression of a wide array of immune ligands. This included the regulation of ligands for the natural killer (NK) cell activating receptors NKG2D and NKp30 (MICA and B7-H6 respectively), which were targeted by US18 and US20. To complement these mechanistic studies, a C-terminal V5 epitope tag was added to each US12 family gene within the HCMV Merlin genome. A large proportion of the US12 family were shown to be degraded within the cell, possibly within lysosomes, which suggests that they may interact with their targets proteins in order to redirect them for degradation. Expression of US12 family members was detectable by immunoblotting during an infection time-course, with many US12 family members expressed during the Tp3 temporal class of HCMV gene expression. Three members of the family were also demonstrated to be N-glycosylated during HCMV infection. The US12 family appear to have associations with the virion assembly compartment, and correspondingly, 7 US12 family members are found within the virion. Furthermore, the majority of the US12 family also show co-localisation with endoplasmic reticulum-derived membranes. These data build on our previous functional characterisation to give insights into the workings of this important HCMV gene family. iii Table of Contents Declarations .............................................................................................................................. i Acknowledgements .................................................................................................................. ii Summary ................................................................................................................................. iii List of Figures .......................................................................................................................... ix List of Tables ............................................................................................................................ x Abbreviations ........................................................................................................................ xiii 1 Introduction .......................................................................................................................... 1 1.1 Herpesviruses ................................................................................................................. 2 1.2 Human Cytomegalovirus (HCMV) .................................................................................. 6 1.3 HCMV Genome .............................................................................................................. 9 1.3.1 HCMV strains ......................................................................................................... 10 1.4 HCMV Life Cycle ........................................................................................................... 16 1.4.1 HCMV Productive Lytic Infection .......................................................................... 16 1.4.1.1 Tropism .......................................................................................................... 16 1.4.1.2 HCMV Entry .................................................................................................... 18 1.4.1.3 Nuclear Transport .......................................................................................... 20 1.4.1.4 Viral Gene Expression .................................................................................... 20 1.4.1.5 Viral DNA Replication ..................................................................................... 24 1.4.1.6 Virus Assembly and Structure ........................................................................ 25 1.4.1.7 Final Envelopment ......................................................................................... 30 1.4.1.8 Virion Egress ................................................................................................... 31 1.4.2 HCMV Latent Infection and Reactivation .............................................................. 31 1.5 HCMV Clinical disease .................................................................................................. 33 1.5.1 Transplant patients ............................................................................................... 34 1.5.2 HIV/AIDs patients .................................................................................................. 35 1.5.3 Congenital infection .............................................................................................. 35 1.5.4 Other at-risk groups .............................................................................................. 36 1.6 HCMV Antiviral Treatments and Vaccines ................................................................... 36 1.6.1 Antiviral treatments .............................................................................................. 36 1.6.2 Vaccines ................................................................................................................ 38 1.6.2.1 Attenuated HCMV vaccines ........................................................................... 39 1.6.2.2 Subunit antigen vaccines ............................................................................... 40 1.6.2.3 Virus like
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