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Virus-Host Interactions in the Early Stages of the Equine Hepacivirus (Eqhv) Lifecycle

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Virus-Host Interactions in the Early Stages of the Equine Hepacivirus (Eqhv) Lifecycle Virus-host interactions in the early stages of the Equine Hepacivirus (EqHV) lifecycle Joseph Robert Lattimer Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds Faculty of Biological Sciences School of Molecular and Cellular Biology September 2017 The candidate confirms that the work submitted is his own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement © 2017 The University of Leeds and Joseph Robert Lattimer The right of Joseph Robert Lattimer to be identified as Author of this work has been asserted by him in accordance with the Copyright, Designs and Patents Act 1988. i Acknowledgements I would firstly like to thank my supervisors Prof. Mark Harris and Prof. Nicola Stonehouse for their continued guidance and support throughout this project. I would also like to thank Dr. Hazel Stewart, Dr. Cheryl Walter, and Dr. Zsofia Igloi for helping me learn the ropes, and for their scientific input at various stages throughout this project. Thank you to the past and present members of Garstang 8.61, with a special mention to Andrew, Chris, Emma, and Lauren, in part for their helpful advice and discussion, but mostly for keeping me sane through four long years! A special thank you also goes out to my parents for supporting me through thick and thin, often having more enthusiasm than I did, and especially for always asking about my project even if they had no idea what I was talking about. A big thank you also goes to Penny for seeing me through the final hurdle, and not complaining when I had to abandon her to go to work. Finally, I would like to thank the Biotechnology and Biological Sciences Research Council (BBSRC) for funding this project. ii Abstract EqHV is the most closely related virus to HCV, and is proposed to have diverged from HCV within the last 1000 years. Studying viruses which share a close evolutionary relationship, yet differ greatly in their ability to cause disease, provides a unique opportunity to facilitate comparative analysis of both replication strategies and pathogenic mechanisms. It has previously been demonstrated that, like HCV, the EqHV 5’UTR functioned as an IRES. Here we set out to undertake a more detailed structural and functional analysis of the 5’UTR. A mutational analysis of the structural features of the EqHV 5′UTR was undertaken to investigate their roles in its function as an IRES. A complementary study utilising 2’ hydroxyl acylation and analysis by primer extension (SHAPE), to experimentally confirm the predicted structure of the EqHV 5’UTR in order to reveal how this related to function, was also conducted. This combined approach revealed that miR122 mediated enhancement of translation was dependent on a seed site located directly upstream of stem-loop (SL) II and that SLI was not required for EqHV IRES mediated translation. SLIII was absolutely essential, as was SLIIId and the conserved GGG motif. An essential role for SLIIIb was demonstrated for translation from an EqHV sub-genomic replicon. SHAPE experiments revealed that the conserved GGG motif was essential for EqHV 5′UTR:40S ribosomal subunit interactions, and that a GTC sequence in the apical loop of SLIIIb mediated an interaction with eIF3. This study also set out to establish an EqHV sub-genomic replicon capable of replicating in vitro in mammalian cells; however, this could not be achieved. When taken with published data it is possible to conclude that current EqHV isolates are not able to replicate in currently available cell culture systems and it is likely that new isolates, or cell lines, will be required to achieve in vitro replication. iii Table of contents Acknowledgements .................................................................................................................... ii Abstract ..................................................................................................................................... iii Abbreviations ........................................................................................................................... xii Chapter 1 Introduction ................................................................................................................. 1 1.1 Overview ............................................................................................................................. 2 1.2 Translation initiation ........................................................................................................... 3 1.2.1 Cap-dependent initiation ............................................................................................. 3 1.2.2 Viral IRES ...................................................................................................................... 6 1.2.3 Hepaciviral IRES ............................................................................................................ 8 1.3 RNA structure and determination .................................................................................... 11 1.3.1 The folding of RNA into secondary and tertiary structures ....................................... 11 1.3.2 Viral RNA structure .................................................................................................... 12 1.3.3 RNA structure prediction software ............................................................................ 13 1.3.4 Selective 2′-hydroxyl acylation analysed by primer extension (SHAPE) .................... 13 1.4 Hepatitis C virus ................................................................................................................ 16 1.4.1 Prevalence, transmission and pathogenicity ............................................................. 16 1.4.2 Organisation of the HCV genome .............................................................................. 16 1.4.3 The HCV viral particle and entry ................................................................................ 17 1.4.4 Polyprotein expression and processing, and replication ........................................... 18 1.4.5 Assembly and release ................................................................................................ 19 1.4.6 The HCV sub genomic replicon .................................................................................. 20 1.5 Equine hepacivirus ............................................................................................................ 21 1.5.1 Discovery and initial characterisation of EqHV .......................................................... 21 1.5.2 Prevalence, host range, and classification, of EqHV .................................................. 23 1.5.3 Transmission, tissue tropism, and pathology, of EqHV ............................................. 24 1.5.4 Molecular biology of EqHV – the story so far ............................................................ 26 1.6 Other newly discovered hepaciviruses ............................................................................. 27 1.6.1 Genomic organisation of the newly discovered hepaciviruses ................................. 27 1.6.2 Tissue tropism, pathology, and prevalence, of the newly discovered hepaciviruses 29 1.6.3 Update to the taxonomy of the hepaciviruses .......................................................... 31 1.6.4 The newly discovered hepaciviruses as a model system to study HCV ..................... 32 1.7 Project aims....................................................................................................................... 34 Chapter 2 Materials and Methods .............................................................................................. 35 iv 2.1 Materials: .......................................................................................................................... 36 2.1.1 Mammalian cell lines ................................................................................................. 36 2.1.2 Bacterial strains .......................................................................................................... 36 2.1.3 Virus sequences ......................................................................................................... 36 2.1.4 SGR constructs ........................................................................................................... 36 2.1.5 Bicistronic expression constructs ............................................................................... 37 2.1.6 miR122 reporter constructs ....................................................................................... 37 2.1.7 N-Methylisatoic anhydride (NMIA) ............................................................................ 37 2.1.8 Purified eIF3 and 40S ribosomal subunit ................................................................... 37 2.1.9 Primers ....................................................................................................................... 37 2.1.10 Tissue culture microscope ....................................................................................... 37 2.2 Nucleic acid manipulation ................................................................................................. 38 2.2.1 Bacterial transformation ...........................................................................................
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