Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2012-07-30T18:02:27Z No. of bitstreams: 1 Marcelo Magalhaes Silva Estudo de alterações genéticas....pdf: 2168493 bytes, checksum: 48c50f165408a4314aa5ad8de3c72ca0 (MD5) / Made available in DSpace on 2012-07-30T18:02:27Z (GMT). No. of bitstreams: 1 Marcelo Magalhaes Silva Estudo de alterações genéticas....pdf: 2168493 bytes, checksum: 48c50f165408a4314aa5ad8de3c72ca0 (MD5) Previous issue date: 2012 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil / A leucemia/linfoma de células T do adulto (ATL) é uma severa doença linfoproliferativa de células T CD4+ associada ao HTLV-1. Por apresentar diferentes manifestações clínicas, essa neoplasia pode ser classificada em cinco formas: aguda, crônica, smoldering, linfomatosa e tumoral primária de pele. Embora alguns trabalhos venham estudando o processo oncogênico mediado pelo HTLV-1, diversos fatores responsáveis pelo desenvolvimento da ATL ainda permanecem desconhecidos. Este estudo teve como objetivo a investigação de alterações genéticas em células ATL (mutações pontuais em genes supressores de tumor e alterações microssatélites) e sua associação com a evolução clínica da doença e sobrevida dos pacientes. A presença de mutações pontuais nos supressores de tumor TP53, p15INK4B e p16INK4A foram avaliadas em 31 pacientes com diferentes formas da ATL (16 agudos, dez crônicos e cinco smoldering) por análise de seqüenciamento de DNA. Cinco pacientes (16%) apresentaram mutações pontuais no gene TP53, sendo que quatro dentre os mesmos foram classificados com a forma aguda. A presença de mutações nos genes avaliados foi associada com pior prognóstico em pacientes com a forma aguda. Em um dos pacientes incluídos neste trabalho (forma aguda) foi verificada a presença de alteração no éxon 2 do gene p16INK4A. Mutações pontuais não foram detectadas no gene p15INK4B em nenhum dos pacientes incluídos. Os marcadores D10S190, D10S191, D11S1391 e D18S21 foram utilizados para a análise de alterações microssatélites por metodologia semi-automatizada. Dentre os 25 pacientes ATL avaliados (seis agudos, oito crônicos, dez smoldering e um linfomatoso), sete apresentaram alterações microssatélites. Três desses pacientes apresentaram instabilidade (MSI), três pacientes apresentaram perda de heterozigosidade (LOH) e em um paciente foi verificado ambas as alterações. Na Bahia, mutações pontuais em TP53 foram detectadas principalmente na forma aguda da ATL e parece estar associada com pior prognóstico. Além disso, de acordo com nossos conhecimentos, este é o primeiro estudo a descrever tanto MSI com LOH em pacientes portando formas crônica e smoldering da ATL. / Adult T-cell leukemia/lymphoma (ATL) is a severe CD4+ lymphoproliferative disease associated to human T-cell lymphotropic virus type 1 (HTLV-1). ATL has different clinical manifestations and is classified in five clinical forms: acute, chronic, smoldering, lymphoma and primary cutaneous tumoral. Although the mechanisms of oncogenesis of the HTLV-1 have been investigated, the factors related to ATL development are still unknown. The goal of this study was to investigate genetic alterations in ATL cells (point mutations in tumor suppressor genes and microsatellite alterations) and their association with the clinical evolution of the disease and survival. The presence of point mutations in TP53, p15INK4B e p16INK4A were evaluated in 31 ATL patients (16 acute, ten chronic and five smoldering) by direct sequencing. Five of them (16%) had TP53 point mutations, four of them with the acute form of ATL. The presence of point mutations in this gene was associated to poor prognosis in acute patients. Only one case (acute form) has an alteration in the exon 2 of the p16INK4A gene. No point mutations of the p15INK4B were found in the patients included. The markers D10S190, D10S191, D11S1391 and D18S21 were considered for the microsatellite analysis using a semiautomated technique. From the twenty-five ATL cases included (six acute, eight chronic, ten smoldering and one lymphoma), seven showed microsatellite alteration. Among them, three patients had microsatellite instability (MSI), three had loss of heterozygosity and one patient presented both alterations. In Bahia, point mutations in TP53 were detected mainly in acute form of ATL and were associated to poor prognosis. The presence of MSI and LOH in the smoldering and chronic forms of ATL were demonstrated for the first time in this study.

La sécurité est devenue un enjeu important dans le développement des systèmes logiciels actuels. La majorité des concepteurs de ces systèmes manquent d’expertise dans le domaine de la sécurité. Il s’avère donc important de les guider tout au long des différentes phases de développement logiciel dans le but de produire des systèmes plus sécurisés. Cela permettra de réduire le temps ainsi que les coûts de développement. Pour atteindre cet objectif, nous proposons d’appliquer l’expertise en matière de sécurité sous forme de patrons de sécurité lors de la phase de conception de logiciels. Un patron de sécurité intègre des solutions éprouvées et génériques proposées par des experts en sécurité. Cependant, les patrons de sécurité sont souvent négligés au niveau de la conception et ne constituent pas une solution intuitive qui peut être utilisée par les concepteurs de logiciels. Cela peut être le résultat de l’inadaptation de ces patrons au contexte des systèmes, la non-expertise des concepteurs dans le domaine de la sécurité ou encore l’absence d’un processus d’intégration de ces patrons dans les modèles à un haut niveau d’abstraction.Afin de permettre aux concepteurs d’utiliser les solutions proposées par des patrons de sécurité, cette thèse propose une approche d’ingénierie dirigée par les modèles pour sécuriser des applications via l’intégration de patrons de sécurité. Nous avons choisi comme contexte d’application de notre approche, les applications à base de composants qui visent à faciliter le développement d’applications à partir de l’assemblage de briques logicielles préfabriquées appelées composants. Le processus proposé assure la séparation entre l’expertise du domaine d’application et l’expertise de sécurité, toutes les deux étant nécessaires pour construire une application sécurisée. La méthodologie proposée assure une intégration semi-automatique des patrons de sécurité dans le modèle initial. Cette intégration est réalisée tout d’abord lors de la modélisation de l’application à travers, dans un premier temps, l’élaboration de profils étendant les concepts du domaine avec les concepts de sécurité. Dans un second temps, l’intégration se fait à travers la définition de règles, qui une fois appliquées, génèrent une application sécurisée. Finalement, cette intégration est assurée aussi au niveau de la génération du code fonctionnel de l’application en intégrant le code non-fonctionnel relatif à la sécurité à travers l’utilisation des aspects. L’utilisation de l’approche orientée aspect garantit que l’application des patrons de sécurité est indépendante de toute application particulière. Le processus proposé est décrit avec le standard SPEM.Ce travail a été concrétisé par un outil nommé SCRI-TOOL pour SeCurity patteRn Integration Tool. Cet outil permet aux développeurs non experts en sécurité d’intégrer les différentes propriétés de sécurité (intégrées dans les patrons) dans une application à base de composants. Afin d’illustrer l’utilisation de SCRI-TOOL, nous proposons une étude de cas portant sur le domaine des systèmes de soins distribués. Le choix d’une telle étude de cas s’explique par l’importance des exigences en termes de sécurité requises pour le bon fonctionnement d’une telle application. En effet, vue le grand nombre d’acteurs pouvant interagir, la sécurité est une exigence critique dans de tels systèmes. Cette étude nous a permis de mettre en évidence l’importance de la gestion de la sécurité à un haut niveau d’abstraction et la façon d’appliquer la méthodologie proposée sur un cas réel. / Security has become an important challenge in current software and system development. Most of designers are experts in software development but not experts in security. It is important to guide them to apply security mechanisms in the early phases of software development to reduce time and cost of development. To reach this objective, we propose to apply security expertise as security patterns at software design phase. A security pattern is a well-understood solution to a recurring information security problem. So, security patterns encapsulate the knowledge accumulated by security experts to secure a software system. Although well documented, patterns are often neglected at the design level and do not constitute an intuitive solution that can be used by software designers. This can be the result of the maladjustment of those patterns to systems context, the inexpertness of designers with security solutions and the need of integration process to let designers apply those pattern ? solutions in practical situations and to work with patterns at higher levels of abstraction. To enable designers to use solutions proposed by security patterns, this thesis proposes a model driven engineering approach to secure applications through the integration of security patterns. Component-based approach is a powerful means to develop and reuse complex systems. In this thesis, we take component based software systems as an application domain for our approach to facilitate the development of applications by assembling prefabricated software building blocks called components. The proposed process provides separation between domain expertise and application security expertise, both of which are needed to build a secure application. Our main goal is to provide a semi-automatic integrating of security patterns into component-based models, and producing an executable secure code. This integration is performed through a set of transformation rules. The result of this integration is a new model supporting security concepts. It is then automatically translated into aspect-oriented code related to security. These aspects are then woven in a modular way within the functional application code to enforce specified security properties. The use of aspect technology in the implementation phase guarantees that the application of security patterns is independent from any particular implementation. In order to provide a clear comprehension of the SCRIP process, we have described it using the standard SPEM . This work is implemented in a software tool called SCRI-TOOL (SeCurity patteRn Integration Tool). This tool allows not security experts developers to integrate different security properties throughout the development cycle of an component based application. To illustrate the use of SCRI-TOOL, we propose a case study regarding electronic healthcare systems. The choice of such a case study is motivated by the great attention archived for such systems from academia and industry and by the importance of security in such systems. Indeed, because of the large number of actors that can interact in such systems, security is a critical requirement. This case study will also allow us to illustrate the proposed methodology to highlight the importance of security management at a high level of abstraction. As results of the application of this process, we obtain a health care application completely secure and meeting the requirements of medical context.

Le virus T lymphotropique humain de type 1 (HTLV-1) est l’agent étiologique d’une forme rare et très agressive de leucémie de l’adulte (ATL). Le processus leucémogène a longtemps été attribué à la seule action de l’oncoprotéine Tax. Cependant, une nouvelle protéine virale, appelée HBZ (HTLV-1 bZIP factor), a été découverte en 2002. Elle est codée par le brin complémentaire du génome proviral et transcrite en antisens à partir du LTR3’. HBZ s’est avéré être un acteur clef de la prolifération et de la transformation des cellules T infectées, et donc du développement de l’ATL. La présente étude propose de nouvelles pistes quant aux mécanismes par lesquels HBZ induit la survie et la prolifération cellulaire. Nous avons montré que la protéine HBZ stimule l’expression de la neurotrophine BDNF et que les cellules de patients ATL surexpriment à la fois BDNF et son récepteur TrkB. De plus, ces patients présentent une concentration sérique anormalement élevée de la forme mature de BDNF, suggérant l’existence d’une boucle autocrine/paracrine BDNF/TrkB. L’activité de cette boucle a été confirmée in vitro et promeut la survie des cellules infectées par HTLV-1. D’autre part, nous avons découvert qu’HBZ dérégule l’expression du suppresseur de tumeur JunD dans les cellules T infectées, et induit celle de l’isoforme potentiellement oncogène ΔJunD. La production de ΔJunD résulterait d’une altération des mécanismes d’initiation de la traduction par HBZ. Nos résultats montrent aussi que ΔJunD promeut la prolifération et la transformation cellulaire en l’absence de sérum. Nous proposons donc que son expression pourrait contribuer à l’évolution des cellules T infectées en cellules leucémiques. / The human T-lymphotropic virus type 1 (HTLV-1) is associated with a rare and aggressive form of adult leukemia (ATL). For a long time, leukemogenesis was thought to mainly result from the action of the Tax oncoprotein. However, a new viral protein, called HBZ (HTLV-1 bZIP factor), was discovered in 2002. It is encoded by the minus strand of the proviral genome and transcribed in antisens from the 3’LTR. Since its discovery, HBZ came out as a key player in proliferation and transformation of infected T cells, thus contributing to ATL development. In this study we provide new leads regarding the mechanisms of HBZ-induced cell survival and proliferation. On one hand, we show that HBZ stimulates the expression of the BDNF neurotrophin and that ATL cells from patients overexpress both BDNF and its high-affinity receptor TrkB. Moreover, sera from patients exhibited abnormal levels of the mature form of BDNF, suggesting the existence of a BDNF/TrkB paracrine/autocrine loop. That loop was confirmed to be activated in vitro and to support the survival of HTLV-1-infected cells. On the other hand, we discovered that HBZ deregulates the expression of the JunD tumor suppressor in infected T cells and induces that of the ∆JunD isoform, which is potentially oncogenic. ∆JunD production would result from alteration of the translational initiation by HBZ. Our results also show that ∆JunD induces proliferation and transformation of serum starved cells. Finally, we hypothesize that HBZ-induced expression of ∆JunD may influence infected T cells to turn leukemic.

Submitted by Sandra Pereira (srpereira@ufrrj.br) on 2018-04-12T12:14:36Z No. of bitstreams: 1 2010 - Juliana Almeida Braga.pdf: 2354270 bytes, checksum: 98c45e0ebd59588dfab79268b972b77f (MD5) / Made available in DSpace on 2018-04-12T12:14:36Z (GMT). No. of bitstreams: 1 2010 - Juliana Almeida Braga.pdf: 2354270 bytes, checksum: 98c45e0ebd59588dfab79268b972b77f (MD5) Previous issue date: 2010-07-15 / The high species richness of the Atlantic and Amazon rainforests places Brazil as one of the most important repositories of biological diversity worldwide. Unfortunately, some of these protected areas were rapidly degraded. Deforestation, cattle and agriculture expansion, the spread of exotic species are listed as key factors that mitigate the environmental. The effects of these factors on the bee fauna in a short span of time can only be roughly estimated, but predictions for the future are potentially catastrophic. This study aimed to evaluate the bee fauna and flora diversity in fragments of Atlantic rainforest, and to provide information about the geodiversity of the fragments. Samples were taken at four sites of fragments over a year from bees visiting plants. From the survey of environmental conditions close to the fragments we obtained the rates of geodiversity. In all fragments, the inventory showed higher species richness of solitary bees and greater abundance of Meliponina. Compared with other surveys of Atlantic forest, there is a low species richness of fauna and flora melitophily, suggesting that the fragments are unfavorable for the maintenance of bees. The statistical model predicts a decline of flora from the data of bee fauna of the fragments. / A alta riqueza de esp?cies na Floresta Atl?ntica posiciona o Brasil como um dos mais importantes reposit?rios da diversidade biol?gica mundial. Infelizmente, parte destas ?reas de prote??o foi rapidamente degradada; o desflorestamento, a explora??o agr?cola, a propaga??o de esp?cies ex?ticas s?o indicados como os principais fatores que mitigam o meio ambiente. Os efeitos destes fatores sobre a fauna de abelhas em curto espa?o de tempo s? pode ser estimado aproximadamente, mas as previs?es para o futuro s?o potencialmente catastr?ficas. Neste estudo, buscou-se avaliar a diversidade da fauna e flora melit?filas em quatro fragmentos da Floresta Atl?ntica e dispor de informa??es sobre a geodiversidade destes fragmentos. As amostragens foram feitas em quatro localidades de fragmentos florestais de Mata Atl?ntica ao longo de um ano, de abelhas em visita ?s plantas. A partir do levantamento das condi??es ambientais pr?ximas aos fragmentos, foram calculados os ?ndices de geodiversidade. Em todos os fragmentos, o invent?rio das abelhas mostrou maior riqueza de esp?cies de abelhas solit?rias e maior abund?ncia relativa de Meliponina. H? uma baixa riqueza de esp?cies de fauna e flora melit?fila, comparada com outros invent?rios de Mata Atl?ntica, sugerindo que os fragmentos s?o pouco favor?veis para a manuten??o das abelhas. O modelo estat?stico previu um decl?nio de flora a partir dos dados de fauna de abelhas dos fragmentos.

Presented work covers one of the most important areas of OMG’s model driven architecture (MDA) – problems of object model transformations. Based on research of OMG specifications and other sources, author analyzes transformation process, states importance of modeling and metamodeling for designing of UML like modeling languages. Research work describes designed PIM ant PSM metamodels of aggregate systems. Structure and syntax of ATL and MTL model transformation languages was introduced. Author gives a short overview of model editors and graphical representation for these languages, created using EMF framework tools. Transformation languages have been compared. A result of experimental transformations was summarized by their qualitative and quantitative criteria. Advantages of hybrid ATL transformation language versus imperative MTL language were found. Experimental transformations were successfully produced and executed using ATL and MTL model transformation languages.

No description available.

No description available.

Le cancer, qui représente la première cause de mortalité en France, a dans environ 25% des cas une origine virale. Dans ce contexte le virus HTLV-1 (Human T-cell Leukemia Virus Type 1) est l'agent étiologique d'une forme très agressive de leucémie et/ou de lymphome appelée ATL (Adult T-cell Leukemia), caractérisée par une grande instabilité génétique et chromosomique. Cette pathologie se développe après une phase asymptomatique de plusieurs décennies et ne connaît à se jour aucun traitement efficace. Parmi l'ensemble des protéines virale, La protéine Tax joue un rôle crucial dans la transformation cellulaire notamment en activant des facteurs de transcription impliqués dans la prolifération et la survie, mais aussi en contrôlant des étapes clefs de la régulation du cycle cellulaire et de la réparation des endommagements de l'ADN. Mon travail de thèse a consisté, dans un premier temps, à étudier le rôle de l'enzyme AID (Activationinduced cytidine deaminase) dans l'instabilité génomique des lymphocytes T. Nos résultats démontrent que AID est exprimée dans les lymphocytes T CD4+ infectés par HTLV-1, que son expression est induite par la protéine virale Tax et que l'enzyme est fonctionnelle. En utilisant différentes techniques nous avons pu démontrer que AID induit une désamination des deoxycytidines en deoxyuraciles in vitro et des endommagements de l'ADN, de type cassures de l'ADN, dans les cellules infectées par HTLV-1 ou transfectées par Tax. L'accumulation de ces endommagements pourrait participer à la transformation cellulaire au cours de l'infection par HTLV-1 suggérant ainsi un rôle de AID dans la leucémogenèse associée à HTLV-1. La longue période de latence avant le développement de l'ATL suggère la mise en place de mécanismes de survie dans les cellules infectées par HTLV-1. Nous avons donc en parallèle étudié les mécanismes de régulation de l'expression de la protéine anti-apoptotique Bfl-1 et son implication dans la survie des cellules infectées / Cancer, which is the leading cause of death in France, has a viral origin in about 25% of cases. In this context, HTLV-1 (Human T-cell Leukemia Virus Type 1) is the etiologic agent of a very aggressive form of leukemia/lymphoma called ATL (Adult T-cell Leukemia), characterized by genetic and chromosomal instability. ATL occurs after an asymptomatic period of several decades and to date there is no effective treatment. Among all the viral proteins, Tax protein plays a crucial role in cell transformation especially by activating transcription factors involved in proliferation and survival, but also by controlling the key steps of the cell cycle regulation and the DNA damage response. The aim of my PhD work was, firstly, to investigate the role of the enzyme AID (activation-induced cytidine deaminase) in the genomic instability of T cells. Our results demonstrate that AID is expressed in HTLV-1-infected CD4+ T cells, that its expression is induced by the viral protein Tax and that AID is functional. Using different techniques we have demonstrated that AID induces deamination of deoxycytidines into deoxyuracils in vitro and DNA damage, like DNA breaks, in HTLV- 1-infected or Tax-expressing cells. Accumulation of DNA damage could be involved in cellular transformation of HTLV-1-infected cells, suggesting a role of AID in leukemogenesis associated with HTLV-1. The long latency period before the development of ATL suggests establishment of survival mechanisms in HTLV-1-infected cells. Thus we studied the mechanisms regulating the expression of anti-apoptotic Bfl-1 protein and its involvement in the survival of infected cells. We have shown that Tax protein induces expression of Bfl-1 via the NF-B and AP-1 pathways, but also that a second viral protein, HBZ, is able to modulate Bfl-1 expression induced by Tax. In addition, the use of Bfl-1 specific shRNA allowed us to highlight the role of Bfl-1 in survival of infected cells as well as in chemoresistance of HTLV-1-infected T cell lines. Thus Bfl-1 appears as a potential therapeutic target in the treatment of ATL

Grâce à sa promesse de réduire les efforts de développement et maintenance du logiciel, l’Ingénierie Dirigée par les Modèles (IDM) attire de plus en plus les acteurs industriels. En effet, elle a été adoptée avec succès dans plusieurs domaines tels que le génie civil, l’industrie automobile et la modernisation de logiciels.Toutefois, la taille croissante des modèles utilisés nécessite de concevoir des solutions passant à l’échelle afin de les traiter (transformer), et stocker (persister) de manière efficace. Une façon de pallier cette problématique est d’utiliser les systèmes et les bases de données répartis. D’une part, les paradigmes de programmation distribuée tels que MapReduce et Pregel peuvent simplifier la distribution de transformations des modèles (TM). Et d’autre part, l’avènement des base de données NoSQL permet le stockage efficace des modèles d’une manière distribuée. Dans le cadre de cette thèse, nous proposons une approche pour la transformation ainsi que pour la persistance de grands modèles.Nous nous basons d’un côté, sur le haut niveau d’abstraction fourni par les langages déclaratifs (relationnels) de transformation et d’un autre côté, sur la sémantique bien définie des paradigmes existants de programmation distribués, afin de livrer un moteur distribué de TM. La distribution est implicite et la syntaxe du langage n’est pas modifiée (aucune primitive de parallélisation n’est ajoutée). Nous étendons cette solution avec un algorithme efficace de distribution de modèles qui se base sur l’analyse statique des transformations et sur résultats récents sur le partitionnement équilibré des graphes. Nous avons appliqué notre approche à ATL, un langage relationnel de TM et MapReduce, un paradigme de programmation distribué. Finalement, nous proposons une solution pour stocker des modèles à l’aide de bases de données NoSQL, en particulier au travers d’un cadre d’applications de persistance répartie. / Model-Driven Engineering (MDE) is gaining ground in industrial environments, thanks to its promise of lowering software development and maintenance effort. It has been adopted with success in producing software for several domains like civil engineering, car manufacturing and modernization of legacy software systems. As the models that need to be handled in model-driven engineering grow in scale, it became necessary to design scalable algorithms for model transformation (MT) as well as well-suitable persistence frameworks. One way to cope with these issues is to exploit the wide availability of distributed clusters in the Cloud for the distributed execution of model transformations and their persistence. On one hand, programming models such as MapReduce and Pregel may simplify the development of distributed model transformations. On the other hand, the availability of different categories of NoSQL databases may help to store efficiently the models. However, because of the dense interconnectivity of models and the complexity of transformation logics, scalability in distributed model processing is challenging. In this thesis, we propose our approach for scalable model transformation and persistence. We exploit the high-level of abstraction of relational MT languages and the well-defined semantics of existing distributed programming models to provide a relational model transformation engine with implicit distributed execution. The syntax of the MT language is not modified and no primitive for distribution is added. Hence developers are not required to have any acquaintance with distributed programming.We extend this approach with an efficient model distribution algorithm, based on the analysis of relational model transformation and recent results on balanced partitioning of streaming graphs. We applied our approach to a popular MT language, ATL, on top of a well-known distributed programming model, MapReduce. Finally, we propose a multi-persistence backend for manipulating and storing models in NoSQL databases according to the modeling scenario. Especially, we focus on decentralized model persistence for distributed model transformations.

Le virus HTLV-1 (Human T-cell Leukemia Virus Type 1) est l’agent étiologique de la Leucémie T de l’adulte (ATL) qui est caractérisée par la prolifération de cellules T CD4+ activées. L’absence de modèle animal fiable reproduisant la leucémogénèse associée à l’infection a ralenti la compréhension des étapes précoces du processus leucémogène et le développement de stratégies thérapeutiques efficaces. Récemment l’amélioration des modèles de souris humanisées a permis la reconstitution d’un système immunitaire humain dans des souris. L’injection de cellules souches hématopoïétiques purifiées à partir de sang de cordon humain dans des souris nouveau-nées de la lignée Rag2-/-γc-/- conduit à la formation de novo de cellules dendritiques, B et T humaines. Ces dernières étant la cible de l’infection par HTLV-1, nous avons infecté des souris humanisées avec des cellules productrices de HTLV-1. Cette inoculation conduit à l’infection stable des cellules humaines dans la souris humanisée et la formation de lymphome ou de leucémie à cellules T humaines activées. Cette infection altère le développement des cellules T dans le thymus conduisant à un phénotype plus mature des thymocytes. Ce modèle animal reproduisant l’infection et la pathogénèse associée nous a permis de suivre l’évolution de la clonalité du virus au sein des différents organes lymphoïdes. Basées sur ces observations, des tests préliminaires ont permis d’étudier une nouvelle approche thérapeutique potentiellement applicable en clinique humaine. Ce travail nous a également permis d’affiner le protocole conduisant à l’humanisation des souris afin d’obtenir une meilleure reconstitution humaine dans ce modèle. / Human T-cell Leukemia Virus type 1 (HTLV-1) is the etiologic agent of the Adult T-cell Leukemia (ATL), an aggressive lymphoproliferation of activated CD4+ T cells. The lack of a reliable small animal model to reproduce in vivo the leukemogenic process associated with HTLV-1 infection has impaired the understanding of the early stages of this process as well as the discovery of effective therapeutic approaches. Recently, improvement in the models of humanized mouse models were achieved allowing the development of a human immune system in mice. Injection of human hematopoietic stem and progenitors cells purified from cord blood into Balb/c Rag2-/-γc-/- newborns allows the de novo production of human dendritic, B and T cells. We infected humanized mice with HTLV-1 producing cell lines resulting in infection of human cells within the mice and the development of lymphomas and leukemias. This infection also results in the alteration of the T-cell development within the thymus pushing the thymocytes toward a more mature phenotype. This small animal model recapitulating in vivo the HTLV-1 infection and its associated pathogenesis gave us the opportunity to study the evolution of the clonality of the virus among human cells in different lymphoid organs. Based on these observations, preliminary results on the use of a new therapeutic approach were obtained. We finally tried to adjust the humanization protocol in order to obtain better engraftment in this model.