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Thesis Reference Thesis Innate immune signaling and the contribution of different regions of capsid to HIV-1 restriction by TRIM5 LASCANO MAILLARD, Maria Josefina Abstract The cellular factor TRIM5α performs a dual role in the innate immunity. First, TRIM5α has an intrinsic ability to induce the AP-1 and NFκB pathways and contributes to the establishment of the LPS-mediated antiviral state. Second, it functions as a restriction factor, blocking early stages of retroviral infection in a capsid-dependent manner. The connections between these two functions of TRIM5α are debated. We investigated the conservation, in TRIM5 orthologues, of the ability to activate the innate immune pathways and analyzed the signification of this function in the context of TRIM5- mediated HIV-1 restriction. We took the advantage that there are seven TRIM5 orthologues in the mouse, with variable abilities to activate the innate immune signaling, to determine the contribution of this signal activator function to the restriction process. [...] Reference LASCANO MAILLARD, Maria Josefina. Innate immune signaling and the contribution of different regions of capsid to HIV-1 restriction by TRIM5. Thèse de doctorat : Univ. Genève, 2014, no. Sc. 4667 URN : urn:nbn:ch:unige-381368 DOI : 10.13097/archive-ouverte/unige:38136 Available at: http://archive-ouverte.unige.ch/unige:38136 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITE DE GENEVE Département de Génétique et Evolution FACULTE DES SCIENCES Professeur François Karch Département de Microbiologie et Médecine moléculaire FACULTE DE MEDECINE Professeur Jeremy Luban Innate immune signaling and the contribution of different regions of capsid to HIV-1 restriction by TRIM5 THESE Présentée à la Faculté des Sciences de l’Université de Genève Pour obtenir le grade de Docteur ès Sciences, mention Biologie par Maria Josefina Lascano Maillard de Bassecourt (JU) Thèse n°4667 Genève 2014 Innate immune signaling and the contribution of different regions of capsid to HIV-1 restriction by TRIM5. Par Maria Josefina Lascano Maillard 1 ABSTRACT The cellular factor TRIM5α performs a dual role in the innate immunity. First, TRIM5α has an intrinsic ability to induce the AP-1 and NFκB pathways and contributes to the establishment of the LPS-mediated antiviral state. Second, it functions as a restriction factor, blocking early stages of retroviral infection in a capsid-dependent manner. The connections between these two functions of TRIM5α are debated. We investigated the conservation, in TRIM5 orthologues, of the ability to activate the innate immune pathways and analyzed the signification of this function in the context of TRIM5- mediated HIV-1 restriction. We took the advantage that there are seven TRIM5 orthologues in the mouse, with variable abilities to activate the innate immune signaling, to determine the contribution of this signal activator function to the restriction process. We found that only the TRIM5 orthologues that could activate the innate immune pathways could restrict HIV-1, when fused to the capsid (CA)-binding cyclophilin A (Cyp or CypA) domain from the owl monkey TRIM5Cyp. While human TRIM5α poses a potent blockade to N-MLV and EIAV infection, HIV-1 is much less affected in in vitro experiments using laboratory-adapted strains. Although certain gag-protease variants arising from clinical isolates show an increased sensitivity to human TRIM5α, the involvement of CA and the regions that influence the recognition of these mutants by the restriction factor are not completely understood. Here, we showed that three regions of the N- terminal domain of HIV-1 capsid are susceptible to modulate the sensitivity to human TRIM5α: the 4th and 7th helices, and the cyclophilin A (CypA)-binding loop. Taken together our data show the importance of TRIM5-mediated activation of the innate immune signaling in retroviral restriction and suggests a complex interplay between CA, CypA and TRIM5α during this process. 2 RESUME Le facteur cellulaire TRIM5α possède une double fonction. Premièrement, TRIM5! montre une capacité intrinsèque d’activer les voies de signalisation cellulaires AP-1 et NFκB et contribue à l’établissement de l’état antiviral enclenché par une stimulation de lipopolisaccharide (LPS). Deuxièmement, il fonctionne en tant que facteur de restriction, en bloquant la réplication rétrovirale à un stage précoce de l’infection, de manière dépendante de la capside (CA). Les connections entre ces deux fonctions de TRIM5α font l’objet de débats. Nous avons analysé la conservation de la fonction activatrice d’immunité innée chez des orthologues de TRIM5α et nous avons tenté de déterminer la signification de cette activité dans le contexte de la restriction rétrovirale. Nous avons exploité différents orthologues murins de TRIM5α qui montrent différentes habiletés à activer les signaux cellulaires de l’immunité innée pour tenter d’établir l’importance de cette fonction dans le processus de restriction. Nous avons trouvé une corrélation entre la capacité d’un orthologue de TRIM5α à activer l’immunité innée et son habileté à bloquer le VIH-1, quand ceux-ci sont fusionnés à un domaine de TRIM5-CyclophilinA (TRIM5Cyp) de l’espèce Aotus trivirgatus, qui lie la capside. Tandis que le TRIM5α humain bloque très fortement la réplication du gammarétrovirus N-MLV et du lentivirus EIAV, le VIH-1 est beaucoup moins affecté au cours d’expériences réalisées in vitro et chez des souches adaptées au laboratoire. Bien que certains virus avec des variantes de séquences de gag-protease montrent une plus grande sensibilité au TRIM5α humain, le rôle de CA et l’influence des différentes regions de CA sur cette susceptibilité ne sont pas clairement établis. Nous avons montrés que trois régions du domaine N-terminal CA sont susceptibles de moduler la reconnaissance par TRIM5α : les hélices 4 et 7, ainsi que la boucle liant la cyclophiline A (CypA). Nos résultats montrent l’importance l’activation de l’immunité innée par TRIM5α dans la restriction rétrovirale et suggèrent une intéraction entre CA, CypA et TRIM5α durant ce processus. 3 Acknowledgments First of all, I Would like to thank my supervisor, Professor Jeremy Luban that alloWed me to conduct a thesis in his lab. We spoke very interesting science together and he supported me even When I had crazy ideas that I Wanted to test! Next, I Want to thank Professor François Karch, to have accepted to be the co- director of my thesis. Thanks to the tWo members of the jury, Dr. Angela Ciuffi and Dr. Dominique Garçin, to have kindly accepted my invitation. A special thanks to the latter that, together With Professor Laurent Roux, our former dear department Director, to have Welcomed me for their lab meetings and have given me advises for my research. Additionally, Dominique’s laugh is contagious! I am also very thankful to Professor William Kelley, because of his kindness and his precious help With the English language corrections on my thesis introduction. Thanks to my friend and colleague, Hanni Bartels. I will never forget the coffees we drank together, or our Pain quotidien on Fridays! Thank you to Manel and Anastasia, to the nice lunches spent together and to have adopted me after my dear friend Hanni moved aWay! I want to thank Madeleine for her sweetness and for the very nice dinners in her beautiful terrasse! Thanks to Stéphane that coached me in my beginnings and that Was of very good support later. It Was nice to speak French With him! Thanks to my other colleagues, Massimo, Alberto, Federico, Christian, Dario, and Jessica. Or should I say (the remaining one noW have the capacity to understand anyWays): Grazie milla! I Wanted to thank my husband Julien for its support and sWeetness during my entire thesis and for being part of my life. He alloWs me to be a better person each day. He also gave the more beautiful present I could have dream of: mi muchachito Augustin, the sunshine of our home! Thanks to my mum and my dad, Adriana and José for all the love they gave to my brothers and me, as Well as for encouraging us in every moments. We are very lucky to have them! Thanks to my brothers Santiago and Clemente for all the great moments We share together and for alWays being present if I need support. 4 Thank you to all my family for making Augustin so happy each time that he goes to visit. Thank you to Geneviève and Jean, for their kindness and for the nice walks in the mountains as Well as the table game moments spent together. Thanks to Anne-Marie, Nina and Patrick, for having me Welcomed in their family, for their sWeetness and for all the good moments spent together! Last but not least, I Would like to dedicate this manuscript to my beloved grandmother Josefina Christe that alWays believed in me and supported me. She will always be present in my heart and thoughts. 5 Table of contents CHAPTER 1 INTRODUCTION 1.1.1 Retroviruses…………………….……………………………………. 10 1.1.2 The discovery of retroviruses and the RT enzyme…..………………. 11 1.1.3 The general structure of retroviruses……………………….………..13 1.1.4 The reverse-transcription process. ….………………………………….. 15 1.1.5 The classification of retroviruses….…………………………………. 17 1.1.6 The Acquired Immunodeficiency Syndrome (AIDS) ………………… 19 1.1.7 The structures of the HIV-1 virion and genome……………………... 22 1.1.8 The HIV-1 life cycle…………….………………………………………27 1.2 TRIM5 and the innate immunity….…………………………………….33 1.2.1 The Pattern-recognition receptors….………………………………..34 1.2.2 The innate immune pathways….…………………………………….38 1.2.3 Immunity to retroviruses: restriction factors……………………......43 1.2.4 TRIM5-mediated retroviral restriction….……………………………50 6 1.2.5 TRIM5 is a PRR….…………………………………….……………..54 1.2.6 TRIM5 in the mouse………………………………….……………..55 1.2.7 TRIM5 take over on the acquired immunity……….………………56 1.3 Aims of the thesis………………………………….………………….57 CHAPTER 2 Introduction….………………………………….………………….……..59 2.1 The link between the two functions of TRIM5: induction of the innate immune signaling and retroviral restriction..………………….….…….………………….……………… 61 2.2 Investigation of the role of murine TRIM5 orthologues as natural restriction factors...………………….….…….………………….………………….
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