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INVESTIGATION INTO SUBGROUP C Felv INTERACTION with ITS HOST RECEPTOR FLVCR1 and the ROLE of FLVCR1 in DIAMOND BLACKFAN ANEMIA

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INVESTIGATION INTO SUBGROUP C Felv INTERACTION with ITS HOST RECEPTOR FLVCR1 and the ROLE of FLVCR1 in DIAMOND BLACKFAN ANEMIA INVESTIGATION INTO SUBGROUP C FeLV INTERACTION WITH ITS HOST RECEPTOR FLVCR1 AND THE ROLE OF FLVCR1 IN DIAMOND BLACKFAN ANEMIA By Michelle Antoinette Rey A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Molecular Genetics University of Toronto © Copyright by Michelle Antoinette Rey 2009 Investigation in subgroup C FeLV interaction with its host receptor FLVCR1 And the role of FLVCR1 in Diamond Blackfan Anemia For the degree of Doctor of Philosophy, 2009 By Michelle Antoinette Rey Graduate Department of Molecular Genetics University of Toronto ABSTRACT Retroviral infection requires an initial interaction between the host cell and the virion. This interaction is predominantly mediated by an envelope (env) protein exposed on the external face of the virion. For gammaretroviruses, such as feline leukemia virus (FeLV), the receptor-binding domain (RBD) is located in the N terminus of env. The RBD forms a distinct domain that is sufficient for binding to the host receptor, but is inefficient in the absence of the corresponding C terminal env, Cdomain, sequence in viral infection studies. I developed a series of hybrid constructs between subgroup C, A and T FeLVs that use distinct receptors for infection to determine the role of Cdom in FeLV binding and infection. Using this approach, I have shown that the C domain (Cdom) of FeLV-C env forms a second receptor-binding domain, distinct from its RBD, which is critical for efficient binding and infection of FeLV-C to host cells expressing FLVCR1. I propose that this mechanism of interaction is conserved for all gammaretroviruses. My results could have important implications for designing gammaretrovirus vectors that can efficiently infect specific target cells. Upon infection with FeLV-C virus, cats develop a disease known as pure red cell aplasia (PRCA). This disease is characterized by a defect in erythropoeisis that results in a decreased number of mature erythroid cells. PRCA has been suggested to be caused by the FeLV-C env binding to and disrupting the host receptor, FLVCR1. Interestingly, feline PRCA is clinically identical to Diamond Blackfan Anemia (DBA), a ii fatal congenital anemia characterized by a specific disruption in erythroid progenitor cellular development. I show that erythroid cells from five DBA patients exhibit low levels of total FLVCR1 transcript expression. In addition, the DBA patients express unique alternatively spliced FLVCR1 transcripts. These alternatively spliced transcripts encode FLVCR1 proteins that are defective in their cellular expression, cell surface localization, and receptor function. Taken together, I propose that the specific anemia observed in DBA is caused by decreased levels of functional FLVCR1 protein due to lowered and alternative splicing of FLVCR1 transcript. iii ACKNOWLEDGEMENTS During the course of my graduate studies, I have overcome many obstacles and challenges with the help and support of family, friends, and co-workers. I would like to extend many thanks and appreciation to those who have encouraged and supported me to continue. First, to my supervisor, Dr. Chetan Tailor, an excellent scientist who gave me a chance to work an exciting project. Thank you for your continued support and guidance in completion of my projects. To the members of the Tailor Lab, thank you for your scientific expertise and brilliant scientific discussions. This research could not have been completed without your help. To Nadia, Johnny and Candy who cheered me on from the sidelines. Thank you for your continued encouragement and praise. To my mother, who was always there for me when I needed her most. Without your continuing support and understanding, I would not have made it this far. Thank you for being my rock solid foundation. Probably one of the greatest benefits during my doctoral degree was the chance to meet the man of my dreams. Richard, you support has helped me so much over the past few years as I have dealt the stress and challenge of finishing my PhD. Thank you for listening, helping and keeping me grounded. Finally, to my darling daughter, Maleeka, who could turn a bad day at the lab, to a wonderful evening at home. The one who always makes me laugh when I felt like crying. As you inch ever nearer to being taller than me, entering your teenage years, know that I so proud of you and that I love you. iv TABLE OF CONTENTS ABSTRACT…………………………………………………………………………............ii ACKNOWLEDGEMENTS…..……………………………………………………............iv TABLE OF CONTENTS………………..………………………………………..………...v LIST OF TABLES…..……………………………………………………………………...ix LIST OF FIGURES……..………………………………………………………………….ix LIST OF ABBREVIATIONS……….……………………………………………………..xi 1. INTRODUCTION…………………………..……………………………….…………..1 1.1 Classification of the retroviridae………………………………………………1 1.2 Retrovirus genome structure…………………………………………………..1 1.3 Life cycle………………………………………………………………………...5 1.4 Lentivirus………………………………………………………………………..6 1.5 Gammaretroviruses.............................................................................................7 1.5.1 Historical perspectives……………………………………………………..7 1.5.2 Categorization of gammaretroviruses……………………………………7 1.5.3 Retrovirus interference…………………………………………………….8 1.5.4 Gammaretrovirus envelope………………………………………………10 1.5.5 Gammaretroviral envelope-receptor interactions…………………….11 1.5.6 Gammaretroviruses and gene therapy………………………………….12 1.6 Feline Leukemia Virus………………………………………………………..13 1.6.1 Origins of FeLV……………………………………………………………13 1.6.2 FeLV structure……………………………………………………………..14 1.6.3 Epidemiology and immune response……………………………………14 1.6.4 FeLV replication and life cycle………………………………………….15 1.6.5 FeLV subgroups…………………………………………………………...16 1.6.5.1 FeLV-A……………………………………………………..16 1.6.5.2 FeLV-T……………………………………………………...17 1.6.5.3 FeLV-B……………………………………………………...18 1.6.5.4 FeLV-C……………………………………………………...18 1.7 Gammaretroviral receptors…………………………………………………..19 1.7.1 Ecotropic MLV receptor, CAT-1........................................................20 1.7.2 Xenotropic and polytropic MLV receptor, XPR1...............................21 1.7.3 RD114, BaEV and type D retrovirus receptor, ASCT2......................21 1.7.4 Receptors for FeLV………………………………………………………..22 1.7.4.1 FeLV-B receptor, Pit1............................................................22 1.7.4.2 FeLV-A receptor, THTR1......................................................23 v 1.7.5 FLVCR1…………………………………………………………………….23 1.7.6 Summary……………………………………………………………………26 1.8 Diamond Blackfan Anemia…………………………………………………...26 1.8.1 Clinical diagnosis and treatment methods of DBA……………………27 1.8.2 Erythropoiesis…………………………………………...…………………28 1.8.2.1 Erythropoietin……………………………………………….29 1.8.2.2 Erythroid cell surface protein expression…………………...31 1.8.2.3 Erythropoiesis in DBA patients……………………………..32 1.8.3 Inheritance and genetics …………………………………………………33 1.8.4 Rps19…………………….………...…………….....................................33 1.8.4.1 Extraribosomal functions of Rps19…………………………34 1.8.5 Other ribosomal proteins linked to DBA……………………………….35 1.8.6 Ribosomal dysfunction and DBA………………………………………..36 1.8.7 FLVCR1 in DBA…………………………………………………………...36 1.8.8 Other bone marrow failure disorders…………………………………...37 1.8.9 Summary…………………………………………………………………….38 2. THE C DOMAIN IN THE SURFACE ENVELOPE GLYCOPROTEIN OF SUBGROUP C FELINE LEUKEMIA VIRUS IS A SECOND RECEPTOR-BINDING DOMAIN…………………………………………………………………………………...39 2.1 Abstract……………………………………….……………………………….40 2.2 Introduction……………………….…………………………………………..40 2.3 Materials and Methods……………………………………………….............42 2.3.1 Cell lines…………………………………………………………………….42 2.3.2 Construction of hybrid envelopes………………………………………..42 2.3.3 Generation of feline cells expressing hybrid FeLV envs……………...45 2.3.4 Viruses and infection studies……………………………….…...………..45 2.3.5 Analysis of surface expression of hybrid FeLV envs…...…….………..46 2.3.6 Analysis of env proteins…………………………………………………...46 2.3.7 SU binding assay…………………………………………………….……..47 2.3.8 Immunoprecipitation of soluble SU………………………….…………..48 2.3.9 C2 peptide synthesis…………………………………………..……………49 2.4 Results…………………………………………………………………………49 2.4.1 Cdom is necessary for efficient interference with FeLV-C virus……49 2.4.2 Cdom controls efficiency of FeLV-C SU binding to CR1….…………52 2.4.3 Cdom is critical for FeLV-C infection of target cells……….………...54 2.4.4 C2 peptide is not sufficient for inhibition of FeLV-C infection….…..58 2.4.5 Co-expression of Cdom with hybrid env enhances infection…….…..58 2.4.6 Soluble Cdom binds to CR1 in the absence of FeLV-C RBD.............58 2.4.7 Cdom does not interfere with FeLV-C infection…………………..…..61 2.5 Discussion……………………………………………………………..............62 vi 3. THE ROLE OF FLVCR1 in DBA…………………………………………………...69 3.1 Abstract………………………………………………………………………....70 3.2 Introduction………………………………………………………………….....70 3.3 Methods and Materials.......................................................................................72 3.3.1 Bone marrow samples..........................................................................72 3.3.2 RNA isolation from CD71high cells.......................................................73 3.3.3 Isolation of FLVCR1, Pit1 and EpoR sequences from DBA and normal erythroid cells......................................................................................73 3.3.4 Construction of HA tagged E3- and E3-E6- retroviral expression constructs…..........................................................................................74 3.3.5 Protein expression profile....................................................................74
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