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Identification and Characterization of Two Novel Syncytin-Like Retroviral Identification and Characterization of Two Novel Syncytin-Like Retroviral Envelope Genes, Captured for a Possible role in the Atypical Structure of the Hyena Placenta and in the Emergence of the Non-Mammalian Mabuya Lizard Placenta a Mathis Funk To cite this version: Mathis Funk. Identification and Characterization of Two Novel Syncytin-Like Retroviral Envelope Genes, Captured for a Possible role in the Atypical Structure of the Hyena Placenta and in the Emergence of the Non-Mammalian Mabuya Lizard Placenta a. Virology. Université Paris Saclay (COmUE), 2018. English. NNT : 2018SACLS106. tel-02377630 HAL Id: tel-02377630 https://tel.archives-ouvertes.fr/tel-02377630 Submitted on 24 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Identification and characterization of 106 S two novel syncytin-like retroviral SACL envelope genes, captured for a 8 possible role in the atypical structure : 201 of the hyena placenta and in the NNT emergence of the non-mammalian Mabuya lizard placenta Thèse de doctorat de l'Université Paris-Saclay préparée à l'UMR 9196, Gustave Roussy École doctorale n°582 cancérologie: biologie, médecine, santé (CBMS) Spécialité de doctorat: aspects moléculaires et cellulaires de la biologie Thèse présentée et soutenue à Villejuif, le 23 mai 2018, par Mathis Funk Composition du Jury : Uriel Hazan Professeur des université, ENS Paris-Saclay (– UMR 8113) Président Jean-Luc Battini Directeur de recherche, IRIM (– UMR 9004) Rapporteur Olivier Schwartz Directeur de recherche, Institut Pasteur (– UMR 3569) Rapporteur Pascale Chavatte-Palmer Directrice de recherche, INRA (– UMR 1198) Examinatrice François Mallet Directeur de recherche, bioMérieux (– EA 7426) Examinateur Thierry Heidmann Directeur de recherche, CNRS (– UMR 9196) Directeur de thèse Acknowledgments I would first like to thank the members of the jury for taking the time to read the present manuscript, which turned out a bit longer than I had planned. I would like to thank Uriel Hazan for accepting to be the president of this jury, book-ending his involvement in my studies. What had started at the ENS Cachan and continued during my Master’s degree at the Institut Pasteur, finally reaches its culmination with the present work, on a topic that Uriel suggested I look into. I would like to sincerely thank Jean-Luc Battini and Olivier Schwartz for their critical reading and evaluation of the present manuscript and their positive feedback. Finally, I want to thank Pascale Chavatte-Palmer and François Mallet, for taking the time to read my work and for accepting to be a part of the jury. I would, of course, also like to thank Thierry Heidmann for giving me the opportunity to work in his laboratory for the past four years, for being always available when I was in need of a guiding hand and present when I needed some prodding. Thank you for not only helping me to get these results, but also for the countless hours we spent to turn them into actual scientific articles. I am grateful to Anne Dupressoir and Gérard Pierron for spending time reading through my manuscript and their words of encouragement and advice. I also want to thank Christa Kuhn for her enthusiasm and encouragement, which played an important part in getting me to where I am today. Je souhaite remercier l’intégralité de l’unité 9196, en particulier Marie et Anne pour avoir partagé leurs savoirs, leurs conseils ainsi que leurs bureaux, Cécile Vernochet pour son aide inestimable, Seila pour son soutien administratif et émotionnel, Grégoire pour son optimisme inébranlable et infectieux, Caroline, Cécile Lemaître et Anthony pour les bon moments passés ensemble, et ce-dernier tout particulièrement pour nos nombreuses discussions (profondes et/ou inutiles) et son énergie aussi inépuisable qu’insupportable. Un grand merci également à Guil- laume, ex-membre de l’unité, pour m’avoir encadré pendant mes débuts et avoir toujours été disponible pour mes questions. J’aimerais remercier le gang des pasteuriens, premiers parmi eux mes ex-colocataires, Matthieu et Thomas, merci de m’avoir supporté pendant ces trois ans et quelques de vie com- mune au 20 avenue d’Ivry, qui s’est transformé en haut-lieu de la science, accueillant maints et maints congrès réunissant la fine fleur de la virologie et de l’immunologie parisienne. I would iii like to thank Oksana, one of the kindest and most generous persons I have had the pleasure to know and someone you can always count on. Merci à Simon l’invisible, ton rétro nous a apporté de nombreuses heures de bonheur. Merci à Vincent le sale cylon pour les côtes de bœuf et à Essia pour ses couscous, toujours aussi bons que son humeur. Merci aux deux Juju pour la bonne ambiance, et je vous souhaite bien du courage, à Juju pour supporter Matthieu et à Juju pour finir ta thèse. Merci aussi à Anaïs, Laura, Cécile, Alix, Marion et tous les autres qui ont rendu la vie parisienne tellement plus agréable. J’aimerais également remercier mes nouveaux ex-colocataires, Raphaël, Ferretti et Viking, pour m’avoir permis de garder l’appartement quelques mois de plus, puis pour m’avoir accueilli sur notre canapé qui, entretemps, était devenu le leur. On a somewhat stranger note I would like to thank all of the friends I have never met, but who have been there to play, talk and just hang out in the virtual parts of this world. Thank you to all sigmas, especially 48, Mori Kaal and koreamax, but also willemd, :goatdrügs:, Cal, and even Thuneral, Slap Chop and Koahi. A great thank you to the Aqueduct Acrobats who have been able to observe my slow and steady descent into placenta and retrovirus induced madness over the past few months, especially Topaz with his awful K/D, expensive haircuts and shared disgust of terrible book adaptations, mrcompson for our academia themed diversions and unmasking the terrible truth behind omics- conferences, and Malloot, everyone’s favorite tactical espionage action ground team leader and platforming liability. I also want to thank Norns and Tarth, our resident Americans, as well as Charisma and Waka. Ich möchte natürlich auch meiner Familie danken, meiner Mutter, meiner Schwester und meinen beiden Brüdern, von deren Hilfe ich immer ausgehen konnte und deren Gesellschaft und Vertrauen mein Leben bereichert haben. Ich danke meiner Oma und meinem Opa für ihre Ermutigungen und Liebe. J’aimerais remercier Patrice, qui a été pour moi pendant ces 25 dernières années le meilleur père que j’aurais pu souhaiter, et qui m’a poussé à être curieux et intéressé en espérant de peut-être, un jour, être aussi instruit et intéressant que lui. Ich möchte hier auch ganz besonders meiner Tante Jutta danken, die innerhalb von ein paar Tagen die ganze Einführung durchgelesen und korrigiert hat. Last but not least, I want to thank all of the people that I have shamefully forgotten to mention here, please forgive me for this oversight. I am still unsure of how I made it this far, but one thing I know: I would not have made it without you. The words above pale in comparison to what I owe you all, I have written and rewritten them many times and I know I’ll never be able to express the feeling appropriately, so all I can do is apologize and say it once more, thank you all so very much. iv Contents Acknowledgments iii Abbreviations xi I Introduction 1 1 Placenta 5 1.1 Challenges of viviparity ............................. 5 1.1.1 Maternofetal exchanges . 5 a. Nutrients 6 b. Oxygen 8 c. Waste 9 1.1.2 Placentation and the maternal immune system . 9 a. Major histocompatibility complex expression 9 b. Uterine natural killer cells 10 c. Adaptive immunity 11 1.1.3 Maternofetal communication . 11 a. Placental hormones 11 b. Extracellular vesicles 12 1.2 Mammalian eutherian placentas ........................ 13 1.2.1 Origin and evolution of the mammalian placenta . 13 a. Monophyletic origin 13 b. Placental diversity 13 1.2.2 Placental types by maternofetal interface . 16 a. Epitheliochorial placentation 18 b. Synepitheliochorial placentation 20 c. Endotheliochorial placentation 22 d. Hemochorial placentation 22 1.3 Viviparity in non-mammalian species ..................... 26 1.3.1 Prevalence of viviparity outside of mammals . 26 v a. Invertebrates 26 b. Non-mammalian vertebrates 27 1.3.2 Examples of non-mammalian placentas . 30 a. Non-vertebrates: the placenta of salps 30 b. Fish: placentation in sharks 31 c. Lizards: placentation in Mabuya and other Scincidae 32 2 Retroviruses 38 2.1 Exogenous Retroviruses ............................. 39 2.1.1 Genomic orgarnisation . 39 a. Non-coding features 39 b. Gag 41 c. Pro and Pol 42 d. Env 44 e. Regulatory and accessory proteins 44 2.1.2 Retroviral phylogeny . 48 a. Subfamily Orthoretrovirinae 48 b. Subfamily Spumaretrovirinae 51 2.1.3 Viral cycle . 53 a. Viral entry 53 b. Reverse transcription 53 c. Genome integration 57 d. Protein expression 60 e. Assembly and budding 61 f. Maturation 64 2.2 Endogenous Retroviruses ............................ 66 2.2.1 Endogenization of retroviral sequences . 67 a. Infection of germinal cells 67 b. Intra-genome spreading of ERVs 69 c. Groups of ERVs 71 2.2.2 Impact of retroviral integration on the host . 72 a. LTR integration can drive ectopic gene expression 72 b.
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  • Assessment and Analysis of the Restriction of Retroviral Infection by the Murine APOBEC3 Protein
    Assessment and Analysis of the Restriction of Retroviral Infection by the Murine APOBEC3 Protein Halil Aydin Thesis submitted to the Faculty of Graduate and Postdoctoral Studies of the University of Ottawa in partial fulfillment of the requirements for the degree of Masters of Science Department of Biochemistry, Microbiology and Immunology Faculty of Medicine ©Halil Aydin, Ottawa, Ontario, Canada, 2011 Learning the rules is hard work and lengthy but playing the game is exciting and fun. John Polanyi Nobel Prize Winner in Chemistry ii ABSTRACT Human APOBEC3 proteins are host-encoded intrinsic restriction factors that can prevent the replication of a broad range of human and animal retroviruses such as HIV, SIV, FIV, MLVs and XMRV. The main pathway of the restriction is believed to occur as a result of the cytidine deaminase activity of these proteins that converts cytidines into uridines in single- stranded DNA retroviral replication intermediates. Uridines in these DNA intermediates disrupt the viral replication cycle and also alter retrovirus infectivity because of the C-to-T transition mutations generated as a result of the deaminase activity on the minus strand DNA. In addition, human APOBEC3 proteins also exhibit a deamination-independent pathway to restrict retroviruses that is not currently well understood. Although the restriction of retroviruses by human APOBEC3 proteins has been intensely studied in vitro, our understanding of how the murine APOBEC3 (mA3) protein restricts retroviruses and/or prevents zoonotic infections in vivo is very limited. In contrast to humans and primates that have 7 APOBEC3 genes, mice have but a single copy. My study of the function and structure of mA3 revealed that it has an inverted functional organization for cytidine deamination in comparison to the human A3G catalytic sites.
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