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Naseer, Asif (2015) Gammaretrovirus Replication in Human Cells: Implications for Experimental Xenografts and Risk of Zoonosis.Phd Thesis

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Naseer, Asif (2015) Gammaretrovirus Replication in Human Cells: Implications for Experimental Xenografts and Risk of Zoonosis.Phd Thesis Naseer, Asif (2015) Gammaretrovirus replication in human cells: implications for experimental xenografts and risk of zoonosis.PhD thesis. http://theses.gla.ac.uk/6279/ . Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Gammaretrovirus replication in human cells: Implications for experimental xenografts and risk of zoonosis Submitted to the University of Glasgow In fulfilment of the requirements of the degree of PhD November 2014 Dr. Asif Naseer, M.B.B.S., PgDip Evidence Based Medicine & HPE. Molecular Oncology Lab Centre for Virus Research Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences 2 Acknowledgement Thank You God for being so merciful and giving me the strength and inspiration required. I would like to thank my supervisors Ewan Cameron and James Neil for giving me the opportunity to undertake this project and for providing me their continuous unlimited support, encouragement, guidance and advice throughout the whole time. I really feel words cannot do justice in expressing my sincere gratitude. I am really grateful to my laboratory supervisor Anne Terry, for her continued assistance and encouragement whenever I needed. By working in the Molecular Oncology Lab, I really feel I had the best colleagues one can ever have. Anna Kilbey was always there to provide all sorts of academic and moral support through all the tough times of PhD. Nancy Mackay was always ready to provide guidance in the lab, and assistance in molecular biology procedures. I would like to thank Margaret Bell for her help in collecting samples, Alma for all sorts of assistance and Kathryn for helping me to interpret the expression analysis experiments. I would also like to thank Gillian Borland for her help in flow cytometry and for all the cakes that always kept me energized while working late hours. I really feel I was really very lucky to find such a friendly place to work. I would also like to thank Karen Blyth and Susan Mason (Beatson) for their regular help in xenograft experiments and Pamela Kearns (University of Birmingham) for kindly providing me precious primary samples and Sam Wilson for his advice in different experiments. I am grateful to the Khyber Medical University for funding my PhD program and Prof Hafiz Ullah for his support and interest in my project. Finally I will like to thank all my friends; Jaffer, Hamid, Inayat, Asif, Yassar, Ahsen, Shahzad, Zia and especially Dr Omar Malik for their moral and spiritual support. Last but not least I will like to thank my family (both in Glasgow and back home in Peshawar) for their patience and support, especially my father Naseer Ahmad and my mother Khalida Khanum who always believed in me and have always encourage me to work hard and my aunt Jameela and uncle Haroon Khan for their support when I needed it the most. 3 Author’s declaration I declare that this thesis is the result of my own work unless otherwise stated. This dissertation has not been submitted for any other degree at the University of Glasgow or any other institute. Part of this thesis has been submitted for publication in the journal ‘Viruses’. 4 Table of contents Acknowledgement .......................................................................... 2 Author’s declaration ....................................................................... 3 Table of contents ........................................................................... 4 List of tables ................................................................................ 8 List of figures ............................................................................... 9 List of techniques I used in this study .................................................. 11 Abbreviations .............................................................................. 13 Abstract ..................................................................................... 16 1 Introduction ........................................................................... 18 1.1 Retroviruses ..................................................................... 18 1.1.1 Structure and classification of retroviruses ........................... 18 1.1.2 Replication cycle of retroviruses ........................................ 20 1.1.3 Exogenous and endogenous retroviruses ............................... 22 1.2 Host resistance .................................................................. 25 1.2.1 The innate and adaptive immune systems ............................ 25 1.2.2 The intrinsic immune system ............................................ 26 1.3 Gammaretroviruses as potential zoonotic agents .......................... 31 1.3.1 Human fossil viruses ...................................................... 31 1.3.2 Koala retrovirus: A recent example of trans-species infection ..... 32 1.3.3 Porcine endogenous retroviruses: A potential zoonotic agent ..... 32 1.3.4 Potentially widespread human exposure to feline leukaemia virus 33 1.3.5 XMRV controversy and its aftermath: XMLV found in human xenografts ............................................................................. 34 1.4 Xenografting and cancer research ........................................... 35 1.4.1 Infection of xenografts ................................................... 35 1.4.2 Retroviral insertional mutagenesis ..................................... 36 1.5 Aims of the study ............................................................... 38 1.5.1 To conduct a prospective study of the risks of acquiring XMLV infection in human cancer xenografts. ........................................... 38 1.5.2 To investigate the susceptibility of human cells to FeLV and XMLV in vitro. 38 1.5.3 To investigate the mechanisms of resistance of human cells to FeLV and XMLV. ............................................................................. 39 1.5.4 To examine the significance of XMLV infection for human xenograft behaviour. ............................................................................. 39 2 Materials and methods .............................................................. 40 2.1 Materials ......................................................................... 40 5 2.1.1 Cell culture ................................................................. 40 2.1.2 Chemically competent bacteria ......................................... 44 2.1.3 Commercial kits ........................................................... 44 2.1.4 Buffers, solutions and reagents ......................................... 45 2.1.5 Enzymes .................................................................... 46 2.1.6 Antibiotics .................................................................. 47 2.1.7 Antibodies .................................................................. 47 2.2 Methods .......................................................................... 47 2.2.1 Infecting cells with virus ................................................. 47 2.2.2 Confirmation of virus infection.......................................... 49 2.2.3 Virus titration .............................................................. 49 2.2.4 Xenografting human cells into mice .................................... 50 2.2.5 Molecular biology .......................................................... 51 3 Infection of human xenografts with XMLV ........................................ 70 3.1 Introduction ..................................................................... 70 3.2 Materials and methods ......................................................... 71 3.3 Results ............................................................................ 71 3.3.1 MCF7 cells xenografted into BALB/c mice become infected with XMLV 71 3.3.2 Primary childhood leukaemia cells passaged in NSG mice show no evidence of XMLV infection. ........................................................ 77 3.3.3 THP-1 cells xenografted into NSG mice do not become infected with XMLV ............................................................................. 78 3.3.4 The Bxv1 provirus is present in BALB/c and C57BL mice but not in NSG mice .............................................................................. 81 3.3.5 MCF7 cells do not get infected with XMLV when passaged in NSG mice but may acquire a non-replication competent defective virus ......... 83 3.3.6 Raji cells xenografted into BALB/c mice formed regressing tumour nodules 88 3.4 Discussion ........................................................................ 88 4 Susceptibility of human cells to XMLV infection ................................. 91 4.1 Introduction ..................................................................... 91 4.2 Materials and methods ......................................................... 91 4.3 Results ............................................................................ 91 4.3.1 XPR1 receptor expression ...............................................
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