En 2016, les lymphoproliférations malignes [lymphome malin non hodgkinien (LNH) et lymphome de Hodgkin (LH)] restent un problème majeur chez les patients porteurs du VIH (PPVIH) car chaque année de 1 à 6 % de ces patients développent des lymphomes. Ces pathologies apparaissent actuellement comme une des principales causes de mortalité chez les PPVIH.Le virus d’Epstein-Barr (EBV), connu de longue date pour son pouvoir immortalisant des lymphocytes B et les propriétés oncogènes de certaines de ses protéines, apparait comme un cofacteur favorisant plus ou moins important de ces lymphomes chez les PPVIH. Quand le virus est présent dans la cellule tumorale ; on parle de cancer associé à l’EBV.Une des questions toujours en suspens est de savoir si la quantification de l’ADN viral EBV (charge virale) et le profil sérologique EBV dans le sang des PPVIH peuvent aider à mieux comprendre la physiopathologie de ces lymphomes et à mieux prendre en charge les PPVIH qui en souffrent.Ce travail de thèse effectuée en co-tutelle entre l’université de Grenoble-Alpes et l’université médicale d’Irkoutsk vise à contribuer à répondre à cette question.La partie bibliographique de cette thèse synthétise (i) les connaissances actuelles sur l’épidémiologie et la physiopathologie des LH (synthèse non publiée en français) et sur le rôle de l’EBV dans les LNH chez les PPVIH (article publié en russe dans « Siberian Medical Journal » en 2015); (ii) les études publiées sur la mesure de la charge virale et la sérologie EBV chez les PPVIH.La partie expérimentale de cette thèse est constituée de trois articles. Le premier article publié dans Journal of Clinical Microbiology en 2016 rapporte la démonstration que l’utilisation d’un standard international développé par l’OMS peut améliorer la précision de la mesure de la charge virale EBV dans le sang. Le deuxième article en cours d’écriture concerne les résultats préliminaires d’une étude de cohorte mise en place par l’ANRS qui suit des PVVIH atteints de LH. Dans cette étude, l’objectif principal était de savoir si la charge virale et la sérologie EBV lors de la découverte du LH pouvaient constituer des marqueurs pronostiques de cette maladie comme cela été décrit dans des LH survenant chez des patients non infectés par le VIH. Nos résultats préliminaires ne vont pas dans ce sens et ces marqueurs ne semblent donc pas utiles pour une amélioration de la prise en charge des LH chez les PPVIH. Le troisième article publié en russe en 2015 dans « HIV infection and Iimmunosuppressive Disorders » décrit l’épidémiologie des lymphomes chez PPVIH de l’Université Médicale d’Irkoutsk. Il montre une importante augmentation des LNH chez les PPVIH entre 2000 et 2014 liée à une épidémie VIH non contrôlée dans cette région de Russie. / In 2016, malignant lymphoproliférations [non Hodgkin's (NHL) and Hodgkin's lymphomas (HL)] remain a major concern in patients living with HIV (PLHIV), that each year 1-6% of these patients develop lymphomas. Lymphomas are the major cause of mortality in this population.Epstein-Bar Virus (EBV), long known for his immortalizing B cells power and oncogenic properties of some of its proteins, emerges as a cofactor favoring lymphoproliferations, more or less important, depending on the type of lymphoproliferation.One of the outstanding questions is whether the molecular and/or serological characterizations of EBV infection may help to better understand the pathophysiology of these diseases and better manage patients suffering from HIV-associated lymphomas.This dissertation under joint supervision between the University Grenoble Alpes and Irkutsk State Medical University aims to answer this question.The literature review of this thesis summarizes: (i) the role of EBV in LNH development in PLHIV (article published in Russian journal “Siberian Medical Journal” in 2015) and the current knowledge on the epidemiology and pathophysiology of Hodgkin's lymphoma (non published in French); (ii) published studies on the EBV viral load and serological evolutions in PLHIV.The experiments consist of three articles. The first article published in Journal of Clinical Microbiology in 2016, reports the demonstration that the application of international standard EBV developed by WHO can improve the quantification of EBV viral load in whole blood. The second study (in writing for publication) contains preliminary results of French National Agency for Research of HIV and hepatitis cohort study investigating PLHIV suffering from Hodgkin's lymphoma. The study focuses on whether the EBV viral load and serology of newly diagnosed lymphoma could provide prognostic information for this disease, as has been described in HIV-negative patients with HL. Our preliminary results don’t support this hypothesis; than EBV markers don’t can be used for best management of HL in PLHIV. The third study published in Russian Journal “HIV infection and Immunosuppressive disorders” (2015) describes the epidemiology of HIV-associated lymphoma in Irkutsk Oblast. The article shows that non-Hodgkin lymphoma incidence rates in PLHIV during 2007-2014 are probably due to HIV epidemic non-controlled in this Russian region.

No description available.

APOBEC3A (Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like editing complex 3 A) appartient à la famille des cytidines désaminases, qui clivent les cytidines en uraciles. APOBEC3G (le modèle de la famille) est un facteur de restriction du VIH : son incorporation dans la particule virale lui permet de désaminer le génome viral néoformé, entrainant hypermutations et dégradation de l’ADN viral. A3A, au contraire, n’est pas incorporée dans la particule virale : la protéine, exprimée spécifiquement dans les cellules myéloïdes de façon inoffensive pour la cellule, agit de la même façon qu’A3G en s’attaquant au virus dès son entrée dans la cellule.Physiologiquement, dans les cellules non-myéloïdes, les APOBEC3 désaminent l’ADN cellulaire simple brin, dont les uraciles sont retirés par UNG2. Les sites abasiques sont clivés par la machinerie de réparation de l’ADN, conduisant parfois à des cassures double-brin et à la mort de la cellule.L’objectif de la thèse était de comprendre cette différence de comportement selon le type cellulaire. Pour cela, des lignées cellulaires inductibles pour A3A ont été créées en cellules HeLa et U937 (monocytaire). Les données obtenues indiquent qu’A3A, partiellement nucléaire, édite l’ADN des cellules en division, conduisant à des dommages à l’ADN, à la production d’espèces réactives de l’oxygène (ROS) et à la mort des cellules. Les cellules différenciées ne présentent pas ce type de dommages, et cela s’explique par une localisation différente de la protéine. Ces résultats permettent de faire pour la première fois le lien entre dommages à l’ADN induits par un membre de la famille des A3 et production de ROS, et donc à l’induction d’une activation immunitaire. Cette activation pourrait avoir des implications dans l’infection ainsi que dans les processus tumorigéniques. / APOBEC3A (Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like editing complex 3 A) belongs to a family of cytidine deaminases that can edit cytidines to uraciles. APOBEC3G (model protein for the family) is a restriction factor for HIV: since it’s incorporated in the viral particle, it can deaminate the newly formed viral genome leading to hypermutation and viral DNA degradation.A3A is not incorporated in the viral particle: this protein is specifically expressed in myeloid cells where it is harmless for the cell and edits the DNA of the incoming viral particle in the same way than A3G.Physiologically, in non-myeloid cells, APOBEC3s deaminate single strand cellular DNA and the resulting uraciles are cut out by UNG2. These abasic sites are cleaved by the DNA repair machinery and can generate double strand breaks that will result in cell death.The objective of the thesis was to understand this difference of behaviour between different cell types. For that purpose, A3A-inducible cell lines were created in HeLa and U937 (monocytic) cells. The results obtained indicate that partially nuclear A3A edits the genomic DNA of cycling cells, leading to DNA damage, to the production of reactive oxygen species (ROS) and to cell death. Differentiated cells do not present this type of damage and that phenotype can be explained by a different localization of the protein.These results link for the first time DNA damage induced by a member of the A3 proteins family to ROS production and to induction of an immune activation. This activation could have implications in infection as well as in tumorigenic processes.

Les cellules Natural Killer (NK) sont des lymphocytes cytotoxiques innés qui jouent un rôle important dans le contrôle immunitaire de la formation de cellules tumorales et de l'infection virale. Chez les personnes en bonne santé, les cellules NK représentent des populations hétérogènes définies par différents marqueurs phénotypiques et exécutant des fonctions spécifiques. Les cellules NK provenant de patients présentant des tumeurs malignes néoplasiques et une infection virale sont cependant typiquement distinctes des personnes en bonne santé par l'apparition de sous-ensembles de cellules NK, qui sont différenciées par leur profil d'isoformes CD45. CD45 est une tyrosine phosphatase leucocytaire commune abondamment exprimée sur toutes les cellules immunitaires hématopoïétiques nucléées. Un variant d'épissage alternatif a entraîné la génération de l'isoforme CD45RA longue et de l'isoforme courte CD45RO, qui s'expriment différemment sur les cellules T naïves et effectrices / mémoires. L'expression des isoformes CD45 sur les cellules NK est largement inconnue. Nous avons précédemment montré que l'expression différentielle des isoformes CD45RA et CD45RO a identifié des sous-ensembles de cellules NK spécifiques dans les maladies hématologiques. Une question reste floue: comment ces cellules CD45RARO + NK changent-elles lorsque leurs cellules cibles disparaissent? Nous avons utilisé des cellules NK de patients traités avec Lenalidomide et l'anticorps anti-CD20 Obinutuzumab pour étudier cela et montré une réduction des cellules CD45RARO / CD45RO + NK après la clairance des cellules tumorales (Chater 4). Nous avons observé la même chose chez les patients atteints de LMA après une chimiothérapie. Dans ce cas, le sous-ensemble de cellules CD45RARO + NK est fortement corrélé avec la trogocytose du marqueur monocyte / macrophage CD14 (Chapitre 5). L'immunophénotypage de cellules NK provenant de patients infectés par le VIH a révélé la présence de cellules CD45RAdim et CD45RO + avec une expression réduite de CD16 et une diminution de la modulation NKG2D totale. En résumé, les cellules NK des cancers hématologiques et l'infection par le VIH présentaient des caractéristiques dysfonctionnelles et l'analyse du profil isoforme CD45 dans ces conditions pathologiques dévoile ces caractéristiques.Enfin, afin de retrouver la réponse immunitaire anti-tumorale chez les patients cancéreux, nous présentons une méthode efficace pour l'expansion in vitro de cellules NK hautement activées à partir du sang du cordon ombilical (UCB). Ces cellules NK prouvent une cytotoxicité cellulaire dépendante des anticorps (ADCC) importante lorsqu'elles sont utilisées en combinaison avec des anticorps monoclonaux approuvés sur le plan clinique ciblant divers antigènes tumoraux. Ceci ouvre leur utilisation dans les immunothérapies à base de cellules NK allogéniques. / Natural Killer (NK) cells are innate cytotoxic lymphocytes that play an important role in immune control of tumor cell formation and virus infection. In healthy people, NK cell represents heterogeneous populations defined by different phenotypical markers and performing specific functions. NK cells from patients with neoplastic malignancies and viral infection are however typically distinctive from healthy people by the appearance of NK cell subsets, which are differentiated by their CD45 isoform profile. CD45 is a common-leukocyte tyrosine phosphatase abundantly expressed on all nucleated hematopoietic immune cells. Alternative splicing variant resulted in generation of the long-isoform CD45RA and the short-isoform CD45RO, which express differently on naïve and effector/memory T cells. Expression of CD45 isoforms on NK cells is largely unknown. We have previously shown that differential expression of CD45RA and CD45RO isoforms identified specific NK cell subsets in hematological diseases. One question remained unclear: how do these CD45RARO+ NK cell changes when their target cells disappeared? We used NK cells from patients treated with Lenalidomide and the anti-CD20 antibody Obinutuzumab to investigate this and showed a reduction in CD45RARO/CD45RO+ NK cells upon clearance of tumor cells (Chater 4). We observed the same in AML patients after chemotherapy. In this case the CD45RARO+ NK cell subset strongly correlates with trogocytosis of the monocyte/macrophage marker CD14 (Chapter 5). Immunophenotyping of NK cells from HIV-infected patients revealed the presence of CD45RAdim and CD45RO+ cells with reduced CD16 expression and total NKG2D down-modulation. In summary, NK cell from hematological cancers and HIV infection displayed dysfunctional hallmarks and analyzing CD45 isoform profile in these pathological conditions unveils these hallmarks.Finally, in order to regain the anti-tumor immune response in cancer patients, we present an efficient method for expansion of highly activated NK cells from umbilical cord blood (UCB) in vitro. These NK cells prove substantial antibody-dependent cell cytotoxicity (ADCC) when used in combination with clinical-approved monoclonal antibodies targeting various tumor antigens. This paves their use in allogeneic NK cell-based immunotherapies.

Les cellules dendritiques plasmacytoïdes (pDC) sont infectées par le VIH-1 et la diminution de leur nombre dans la circulation sanguine est corrélée avec la virémie des patients. Au cours de mes travaux de thèse, nous avons montré que les anticorps neutralisants (AcN) spécifiques du VIH-1 inhibent l’infection des pDC par des isolats primaires de VIH-1. Contrairement aux mDC, le mécanisme d’inhibition de l’infection des pDC est indépendant du RFcγII présent à leur surface. En parallèle, nos résultats indiquent que les pDC produisent de l’interféron-α et d’autres cytokines et chimiokines en réponse au VIH-1, même lorsque l’infection des cellules est inhibée par les AcN. Enfin, nous avons observé l’inhibition du transfert en cis et en trans du VIH-1 des pDC aux lymphocytes T CD4 par les AcN.Dans un contexte d’induction d’AcN par vaccination, l’inhibition de la réplication du VIH-1 dans les pDC associé au maintien de la sécrétion de cytokines pro-inflammatoire par ces cellules pourrait favoriser l’élimination du virus et ralentir sa dissémination dans l’organisme. / Plasmacytoid dendritic cells (pDC) are able to replicate HIV-1, and the decrease of pDC number in blood is correlated with HIV-1 viremia in patients. During my thesis, we showed that HIV-1-specific neutralizing antibodies (NAb) inhibited the infection of pDC by HIV-1primary isolates. Unlike mDC, the mechanism of inhibition of pDC infection was independent of FcγRII expressed on these cells. In parallel, our results indicated that pDC produce interferon-α and other cytokines and chemokines in response to HIV-1, even when HIV-1 infection of these cells was inhibited by NAb. Finally, we showed that NAb were able to inhibit HIV-1 transfer in cis and trans from pDC to CD4 T cells.In the context of antibodies induction by vaccination, the inhibition of HIV-1 replication in pDC associated with the maintenance of pro-inflammatory cytokines released by these cells may help to eliminate the virus and impede its dissemination in the body.

A situação da vulnerabilidade a que estão expostas as crianças que vivem com aids, leva a refletir como e qual a melhor forma de tentar compreender como são abordadas as questões relativas ao seu modo de viver. Conversar com as crianças afetadas, ouvindo-as, torna-se fundamental para a compreensão da situação de doença e também como percebem o seu cotidiano. Para tanto se desenvolveu um estudo exploratório descritivo, com abordagem qualitativa, cujo objetivo foi conhecer a partir da voz da criança que vive com HIV/aids as implicações no seu cotidiano. O estudo foi realizado no período entre novembro de 2012 e março de 2013 e contou com a participação de cinco crianças com HIV/aids, com idades entre 11 e 12 anos. Foi desenvolvido na Organização Não-Governamental (ONG) Mais Criança no município de Porto Alegre/RS. As informações foram coletadas por meio de uma entrevista semi estruturada após aprovação do Comitê de Ética em Pesquisa da UFRGS (109.149) O material resultante das entrevistas foi submetido à análise temática de conteúdo que evidenciou as seguintes categorias: Temores: a tristeza inconstante e Experiências: o conhecimento vivido. Evidenciou-se que em relação ao seu cotidiano elas relatam que não tem uma vida diferente das demais crianças. Elas não deixam de fazer suas atividades diárias em virtude de ter que conviver com o HIV/aids ou ter que tomar as medicações, por mais que essa questão apareceu como uma implicação no seu modo de vida, além de manifestarem expectativas positivas no futuro. A interrupção ou mesmo a necessidade de adiar uma atividade em função de ter que tomar as medicações antirretrovirais, já está introjetada no seu viver, demonstrado pelo relato de um convívio de forma tranquila. A aproximação com essas crianças que vivem uma situação complexa e permeada de conflitos sérios, como seus medos, temores, esperanças, possibilitou conhecer as implicações do seu viver cotidiano. Ressalta-se a importância para os profissionais da saúde em geral, e em especial a enfermagem, de desenvolver estratégias para a criação de um vinculo que possibilite a criança e sua família expor sentimentos e situações que auxilie na condução do processo de viver com essa doença. / The vulnerable situation that children who live with AIDS are exposed to, leads to reflect about how and what is the best way to try to comprehend how the issues about their way of life are dealt with. Talking to affected children, and listening to them, becomes essential to understand the situation of the disease and it is also the way they notice their daily. For that was developed a descriptive exploratory study, with a qualitative approach whose objective learn from the voice of the child living with HIV / aids implications in their daily.The study was conducted between November 2012 and March 2013 and counted with the participation of five children with HIV / AIDS, aged between 11 and 12 years old. It was developed in the Non-Governmental Organization (NGO) More Child in Porto Alegre / RS. The data were collected through a semi-structured interview after approval of the Ethics Committee in Research of UFRGS (109 149). The resulting material was subjected to thematic content analysis interviews that showed the following categories: Fears: constant sadness and Experiences: lived knowledge. In relation to their day by day, they report that they do not have a different life from other children. They do not stop doing their daily activities as a result of having to live with HIV / AIDS or having to take the medications, even though this question appeared as an implication in their way of life, and to express positive expectations in their future. The interruption or even the need to postpone an activity due to having to take antiretroviral medications is already entrenched in their behavior, demonstrated by the report of a smoothly convivial. The approach to these children who live a complex situation, fraught with serious conflicts, such as fears, and hopes, helped understand the implications for the quality of their daily lives. Emphasizes the importance for health professionals in general, and particularly nursing, to develop strategies for creating a bond that allows the child and his family show feelings and situations to assist in driving the process of living with this disease. / La situación de vulnerabilidad a que están expuestos los niños que viven con el SIDA, lo que lleva a reflexionar cómo y qué mejor manera de tratar de entender la forma en que se tratan temas relacionados con su manera de vivir. Hable con los niños afectados, escuchándolos, es esencial para la comprensión de la enfermedad y también la forma en que perciben su diario. Para ello se desarrolló un estudio exploratorio descriptivo con abordaje cualitativo, cuyo objetivo fue aprender de la voz del niño que vive con las consecuencias del VIH / SIDA en su diario. El estudio se llevó a cabo entre noviembre de 2012 y marzo de 2013 y contó con la presencia de cinco niños con VIH / sida, con edades comprendidas entre los 11 y 12 años. Fue desarrollado en la Organización No Gubernamental (ONG) más Niños en Porto Alegre / RS. Los datos fueron recolectados a través de una entrevista semi-estructurada, con la aprobación del Comité de Ética en Investigación de la UFRGS (109 149). El material resultante se sometió a las entrevistas de análisis de contenido temático mostraron que las siguientes categorías: Los miedos: tristeza inconstante y Experiencias: conocimiento vivió. Era evidente que en relación con su informe diario que no tienen una vida diferente a los otros niños. No dejan de hacer sus actividades diarias como consecuencia de tener que vivir con el VIH / SIDA o el tener que tomar medicamentos, a pesar de que esta cuestión apareció como una consecuencia de su modo de vida, y para expresar expectativas positivas. La interrupción o la necesidad de posponer una actividad debido a tener que tomar medicamentos antirretrovirales, ya está arraigada en su comportamiento, como lo demuestra el informe de una convivencia sin problemas. El enfoque de estos niños que viven un proceso complejo y plagado de conflictos graves, como miedos, temores, esperanzas, ayudado entender las implicaciones para la calidad de su vida cotidiana. Hace hincapié en la importancia de que los profesionales de salud en general, y en especial de enfermería, el desarrollo de estrategias para la creación de un vínculo que le permite al niño y sus sentimientos y situaciones que muestran la familia para ayudar en la conducción del proceso de vivir con esta enfermedad.

Este estudo insere-se na linha de pesquisa Fundamentos e Práticas de Enfermagem em Saúde da Mulher, Criança e Adolescente e está vinculado ao Grupo Cuidado à Saúde nas Etapas da Vida (CEVIDA) do Programa de Pós-Graduação em Enfermagem da Universidade Federal do Rio Grande do Sul (UFRGS). Aborda as vivências, repletas de desafios oriundos das demandas de cuidados permanentes com o HIV, do adolescente, que vive com HIV/aids, muitas vezes tensionado pela fase da vida. Assim, teve-se como objetivo: conhecer as trajetórias de cuidado e experiências do adolescente que vive com HIV/aids e sua família, identificando elementos de cuidado à saúde necessários para o enfrentamento do viver com HIV. Pesquisa qualitativa, com a utilização do Método Criativo e Sensível a partir do desenvolvimento da dinâmica Livre para Criar, aprovada pelo Comitê de Ética em Pesquisa da UFRGS CAAE: 14141313.5.0000.5347. Os cenários de coleta de informações foram uma Organização não Governamental (ONG) e um Hospital Público, localizados no município de Porto Alegre, Estado do Rio Grande do Sul. Os participantes foram: 18 adolescentes de 13 a 20 anos de idade e 21 familiares/cuidadores de 23 a 71 anos de idade. A coleta de informações ocorreu no período de abril a julho de 2013. A pesquisa ocorreu em três momentos. Primeiro: imersão em produções realizadas sobre a temática adolescente que vive com HIV/aids e família. Segundo: coleta de informações com adolescente e familiar/cuidador, a partir do desenvolvimento de dinâmica. Terceiro: proposta elencar elementos de Cuidado à Saúde do adolescente que vive com HIV/aids e sua família, com a apresentação dos resultados aos participantes para possíveis sugestões. Para a interpretação das informações realizou-se Análise Temática do Conteúdo. Os resultados foram expressos em categorias: Adolescência e Sexualidade: possibilidades de espaços de comunicação com o familiar/cuidador e adolescente, práticas do cuidado de si e do outro. Tratamento e Medicamento: melhorias na apresentação medicamentosa. Discriminação: espaços sociais e meios de comunicação que desenvolvam discussões de prevenção à discriminação. Revelação do diagnóstico por pessoa com vínculo com o adolescente, principalmente mãe ou pai, com presença ou orientações do serviço de saúde e quando começarem os questionamentos sobre questões relativas à doença: direitos humanos e cidadania, deveres dos adolescentes com o cumprimento do tratamento e direitos legais ― trabalho e benefícios para a manutenção de sua saúde. Adolescente e família (re)pensando sobre as discussões em grupo, os participantes estavam de acordo com maioria dos resultados apontados por eles, sendo sinalizado algumas questões referentes ao tratamento e medicamento, discriminação e direitos humanos e cidadania. No sentido de transformar, efetivar e fortalecer as práticas de cuidado é imprescindível a convergência das políticas públicas, educação nos diferentes níveis e assistência. Destaca-se a relevância do envolvimento da enfermagem em equipe interdisciplinar, promovendo espaços individuais e coletivos para auxiliar e orientar o adolescente e família sobre os caminhos de cuidado à saúde. / This study fits into the research line named Foundations and Practices of Nursing in Health for Women, Children and Adolescents and it is linked to the Health Care in Life Stages Group (CEVIDA) of the Post-Graduation Program in Nursing of the Federal University of Rio Grande do Sul (UFRGS). It approaches the life experiences full of challenges deriving from the demands of permanent care with HIV of the adolescent with HIV/AIDS who is many times stressed by this life stage. Thus, it aimed at know the care trajectories and experiences of the adolescent who lives with HIV/AIDS and his/her family, recognize health care element necessary to copying the to live with HIV. It is a qualitative research by utilizing the Creative and Sensitive Method starting from the development of the Free to Create dynamics, approved by the Ethics Committee in Research of UFRGS CAAE: 14141313.5.0000.5347. The settings to collect information collection were: Non-Governmental Organization and Public Hospital, located in the municipality of Porto Alegre, State of Rio Grande do Sul. The participants were 13 to 20 years-old 18 adolescents and 21 family member/caretaker who were 23 to 71 years of age. The collection of information was carried out from April to July 2013. The research took place upon three moments. First: immersion in productions performed about the theme of the adolescent with HIV/AIDS and his/her family. Second: collection of information with the adolescent and family member/caretaker starting from the development of the dynamics. Third: proposing the elaboration of health care elements for the adolescent who lives with HIV/AIDS and his/her family with the presentation of the results to the participants for possible suggestions. The interpretation of the information was done by Thematic Analysis of the Content. The results were expressed in categories: Adolescence and Sexuality: possibilities of communication spaces with the family member/caretaker and adolescent; practices of self-care and care of the other subject. Treatment and Medication: improvements in the medication presentation. Discrimination: social spaces and means of communication that develop discussions on prevention and discrimination. The disclosure of the diagnosis per person who has bond with the adolescent, mainly the mother or the father, with presence or guidelines from the health service and when inquiries start with questions regarding the disease: human rights and citizenship, duties of the adolescents regarding fulfillment of the treatment, and legal rights – work and benefits for maintaining his/her health. Adolescent and family thinking about discussion in the group, the participants agreed with most of the results pointed out by them, by signaling some of the questions regarding the treatment and the medication, discrimination and human rights and citizenship. In order to transform, to carry out and to strengthen care practices, it is needed the convergence of public policies, education at different levels and assistance. The relevance of the nursing commitment stands out within an interdisciplinary staff, by promoting individual and collective spaces in order to help and to guide the adolescent and the family about health care paths. / Este estudio se inserta en la linea de pesquisa Fundamentos y Prácticas de Enfermería en Salud de la Mujer, niños y Adolescente y está vinculado al Grupo Cuidado a la Salud en las Etapas de la Vida (CEVIDA) del Programa de Pos Grado en Enfermería de la Universidad Federal de Río Grande del Sur (UFRGS). Enfoca las vivencias, llenas de retos oriundos de las demandas de cuidados permanentes con el SIDA, del adolescente, que vive con SIDA/aids, muchas veces tensionado por la fase de la vida. Así, se objetivó: conocer los caminos de cuidado y experiencias del adolescente que vive com SIDA/aids y su familia, identificando elementos de cuidado a la salud necesarios para el afrontamiento del vivir con SIDA. Pesquisa cualitativa, con la utilización del Método Creativo y Sensible desde el deserrollo de la dinámica Libre para Crear, aprobada por el Comité de Ética en Pesquisa de la UFRGS CAAE: 14141313.5.0000.5347. Los escenarios de coleta de informaciones fueron una Organización no Gobernamental (ONG) y un Hospital Público, ubicados en la municipalidad de Porto Alegre, Estado de Río Grande del Sur. Los participantes fueron: 18 adolescentes de 13 a 20 años de edad y 21 familiares/cuidadores de 23 a 71 años de edad. La recopilación de información ocurrió en el período de abril a julio de 2013. La búsqueda ocurrió en tres momentos. Primero: imersión en producciones hechas sobre la temática adolescente que vive con SIDA/aids y familia. Segundo: recopilación de informaciones con adolescente y familiar/cuidador, desde el desarrollo de dinámica. Tercero: propuesta enumerar los elementos de Cuidado a la Salud del adolescente que vive com SIDA/aids y su familia, con la presentación de los resultados a los participantes para posibles sugerencias. Para la interpretación de las informaciones se hizo un Análisis Temático del Contenido. Los resultados fueron expresados en categorías: Adolescencia y Sexualidad: posibilidad de espacios de comunicación con el familiar/cuidador y adolescente, prácticas del cuidado de sí y del otro. Tratamiento y Medicamento: mejoras en la presentación medicamentosa. Discriminación: espacios sociales y medios de comunicación que desarrollen debates de prevención a la discriminación. Divulgación del diagnóstico por persona con vínculo con el adolescente, principalmente madre o padre, con presencia u orientación del servicio de salud y cuando comenzar las preguntas sobre cuestiones relativas a la enfermidad: derechos humanos y ciudadanía, deberes de los adolescentes con el cumplimiento del tratamiento y los derechos legales ― trabajo y beneficios para la manutención de su salud. Elementos del cuidado a la salud del adolescente que vive con SIDA/aids: sugestión del adolescente y familiar/cuidador, los participantes estaban de acuerdo con la mayoría de los resultados apuntados por ellos, siendo sinalizado algunas cuestiones referentes al tratamiento y medicamento, discriminación y derechos humanos y ciudadanía. Para transformar, efectuar y fortalecer las prácticas de cuidado es esencial la convergencia de las políticas públicas, educación en los diferentes niveles y asistencia. Se destaca la relevancia de la participación de la enfermería en equipo interdisciplinario, promoviendo espacios individuales y colectivos para ayudar y guiar al adolescente y familia sobre los caminos de cuidado a la salud.

L'immunité, un système de défense incroyable, protège la plupart des organismes vivants des pathogènes nuisibles. Les composantes innée et acquise de l'immunité travaillent ensemble pour assurer une protection efficace de l'homme ainsi que de tous les autres vertébrés à mâchoires. Les cellules dendritiques, la composante de l'immunité innée, passent régulièrement en revue les tissus périphériques, capturent et traitent les agents pathogènes envahisseurs et enfin, présentent les antigènes aux lymphocytes T pour stimuler les réponses immunitaires adaptatives spécifiques. Ces cellules reconnaissent les organismes étrangers à l'aide de plusieurs "Pattern Recognition Receptors" (PRRs), qui se lient spécifiquement à des molécules à la surface des agents pathogènes, dits "Pathogen Associated Molecular Patterns (PAMPs). Parmi les PRR, les récepteurs lectine de type C (CLRs) ont un rôle important dans la reconnaissance et dans la capture des pathogènes. Cependant, DC-SIGN, l'un de ces CLR, peut être détourné par de nombreux agents pathogènes dangereux, y compris le VIH, afin de promouvoir leur infection. Ce travail vise à développer des antagonistes de DC-SIGN, qui serait en mesure de bloquer l'utilisation de ce récepteur par des agents pathogènes. Pour atteindre cet objectif, la stratégie du développement de ligands glycomimétique de DC-SIGN et la présentation multivalente des glycomimétiques monovalents sélectionnés a été employée. Les études présentées ont été réalisées en collaboration avec plusieurs groupes de chimistes, qui ont conçu et synthétisé différents composés glycomimétiques ainsi que différentes plates-formes multivalentes. Des ligands monovalents de DC-SIGN basés sue le mannose, le fucose et sur les composés C-glycosidiques ont été explorés et différentes plates-formes de valence avec différents modes de présentation dans l'espace ont été étudiées. En utilisant la résonance plasmonique de surface (SPR), l'activité des composés à inhiber DC-SIGN a été estimée. De plus, les composés ont été évalués pour leur sélectivité pour DC-SIGN par rapport à la Langerine, un autre CLR ayant un rôle protecteur contre l'infection par le VIH. Certains de ces composés ont été caractérisés par cristallographie aux rayons X et par spectrométrie RMN. Les études de SPR de composés multivalents ont confirmé l'amélioration de l'activité, mais a également révélé des complications possibles. Dans l'ensemble, ces études ont permis d'identifier les deux meilleurs nouveaux composés et de suggérer des perspectives pour l'amélioration de ces composés et des plates-formes de présentation multivalentes. / An amazing defense system, the immunity, protects most of the living organisms from harmful pathogens. The innate and acquired immunity components work together to provide efficient protection of humans as well as all other jawed vertebrates. Dendritic cells, the component of the innate immunity, routinely survey the peripheral tissues, capture and process the invading pathogens, and finally, present the antigens to the T cells to boost the pathogen specific adaptive immune responses. These cells recognize the foreign organisms with the help of multiple pattern recognition receptors (PRRs), which specifically bind molecules on the pathogen surfaces, so-called pathogen associated molecular patterns (PAMPs). Among PRRs, the C-type lectin receptors (CLRs) have an important role in pathogen recognition and capturing. However, one of these CLRs, DC-SIGN, has been shown to be hijacked by many dangerous pathogens, including HIV, to promote their infection. This work aims to develop the antagonists of the C-type lectin receptor DC-SIGN, which would be able to block the use of this receptor by pathogens. To achieve that, the strategy of the development of glycomimetic ligands of DC-SIGN and the multivalent presentation of the selected monovalent glycomimics has been employed. The presented studies were accomplished in collaboration with several chemists groups, who have designed and synthesized different glycomimetic compounds as well as different multivalent platforms. The mannose-based, fucose-based and the C-glycosidic compounds were explored as monovalent DC-SIGN ligands, and multivalent platforms with different valence as well as ligand presentation in space were investigated. Using surface plasmon resonance (SPR), the activity of the compounds to inhibit DC-SIGN was estimated. Moreover, the compounds were evaluated for their selectivity to DC-SIGN vs langerin, another CLR with a protective role from HIV infection. Some of the compounds were structurally characterized by X-ray crystallography and NMR spectrometry studies. The SPR studies of multivalent compounds confirmed the improved activity, but also revealed possible complications Overall, these studies allowed to identify two new monovalent leads and to draw perspectives for their further improvement, and suggested the improvement of multivalent presentation platforms.

L’Integrase du VIH est une ADN recombinase catalysant deux réactions qui permettent l'intégration de l'ADN viral dans l'ADN hôte. L’intégrase du VIH comprend 3 domaines : N-terminal impliqué dans la réaction de « 3' processing » et le transfert de brin, le domaine catalytique contenant le site actif et le domaine C-terminal liant l'ADN non-spécifiquement (CTD). Des recherches récentes mettent en évidence l'importance du CTD dans la liaison avec d'autres protéines virales comme la transcriptase inverse. Le but de la thèse était de comprendre les rôles et l'importance du domaine C-terminal de l’intégrase dans deux contextes : l'intégration dans la chromatine et la coévolution, avec l'objectif de comprendre le rôle de la multimerisation dans la fonction de l’intégrase. Globalement, les résultats de mon projet indiquent que l'IN-CTD joue un rôle important, en contribuant à la formation de multimères d'ordre supérieur importants pour la fonction de l’IN. / HIV Integrase is a DNA recombinase that catalyzes two endonucleolytic reactions that allow the viral DNA integration into host DNA for replication and subsequent viral protein production. HIV Integrase consists of 3 structural and functional domains: The N-terminal zinc domain involved in 3’ processing and strand transfer, the catalytic core domain which contains the active site, and the C-terminal domain that binds DNA non- specifically. Recent research highlights the importance of the CTD in binding with other viral proteins such as Reverse Transcriptase. The aim of the thesis was to understand the roles and importance of the C-terminal domain of HIV-1 Integrase in two contexts: chromatin integration, and co-evolution, with the overall purpose of understanding the role of multimerization in IN function. Overall, results from my project indicate that the IN-CTD plays an important role, by contributing to the formation of higher order multimers that are important for IN functionality.

Este estudo insere-se na linha de pesquisa Fundamentos e Práticas de Enfermagem em Saúde da Mulher, Criança e Adolescente e está vinculado ao Grupo Cuidado à Saúde nas Etapas da Vida (CEVIDA) do Programa de Pós-Graduação em Enfermagem da Universidade Federal do Rio Grande do Sul (UFRGS). Aborda as vivências, repletas de desafios oriundos das demandas de cuidados permanentes com o HIV, do adolescente, que vive com HIV/aids, muitas vezes tensionado pela fase da vida. Assim, teve-se como objetivo: conhecer as trajetórias de cuidado e experiências do adolescente que vive com HIV/aids e sua família, identificando elementos de cuidado à saúde necessários para o enfrentamento do viver com HIV. Pesquisa qualitativa, com a utilização do Método Criativo e Sensível a partir do desenvolvimento da dinâmica Livre para Criar, aprovada pelo Comitê de Ética em Pesquisa da UFRGS CAAE: 14141313.5.0000.5347. Os cenários de coleta de informações foram uma Organização não Governamental (ONG) e um Hospital Público, localizados no município de Porto Alegre, Estado do Rio Grande do Sul. Os participantes foram: 18 adolescentes de 13 a 20 anos de idade e 21 familiares/cuidadores de 23 a 71 anos de idade. A coleta de informações ocorreu no período de abril a julho de 2013. A pesquisa ocorreu em três momentos. Primeiro: imersão em produções realizadas sobre a temática adolescente que vive com HIV/aids e família. Segundo: coleta de informações com adolescente e familiar/cuidador, a partir do desenvolvimento de dinâmica. Terceiro: proposta elencar elementos de Cuidado à Saúde do adolescente que vive com HIV/aids e sua família, com a apresentação dos resultados aos participantes para possíveis sugestões. Para a interpretação das informações realizou-se Análise Temática do Conteúdo. Os resultados foram expressos em categorias: Adolescência e Sexualidade: possibilidades de espaços de comunicação com o familiar/cuidador e adolescente, práticas do cuidado de si e do outro. Tratamento e Medicamento: melhorias na apresentação medicamentosa. Discriminação: espaços sociais e meios de comunicação que desenvolvam discussões de prevenção à discriminação. Revelação do diagnóstico por pessoa com vínculo com o adolescente, principalmente mãe ou pai, com presença ou orientações do serviço de saúde e quando começarem os questionamentos sobre questões relativas à doença: direitos humanos e cidadania, deveres dos adolescentes com o cumprimento do tratamento e direitos legais ― trabalho e benefícios para a manutenção de sua saúde. Adolescente e família (re)pensando sobre as discussões em grupo, os participantes estavam de acordo com maioria dos resultados apontados por eles, sendo sinalizado algumas questões referentes ao tratamento e medicamento, discriminação e direitos humanos e cidadania. No sentido de transformar, efetivar e fortalecer as práticas de cuidado é imprescindível a convergência das políticas públicas, educação nos diferentes níveis e assistência. Destaca-se a relevância do envolvimento da enfermagem em equipe interdisciplinar, promovendo espaços individuais e coletivos para auxiliar e orientar o adolescente e família sobre os caminhos de cuidado à saúde. / This study fits into the research line named Foundations and Practices of Nursing in Health for Women, Children and Adolescents and it is linked to the Health Care in Life Stages Group (CEVIDA) of the Post-Graduation Program in Nursing of the Federal University of Rio Grande do Sul (UFRGS). It approaches the life experiences full of challenges deriving from the demands of permanent care with HIV of the adolescent with HIV/AIDS who is many times stressed by this life stage. Thus, it aimed at know the care trajectories and experiences of the adolescent who lives with HIV/AIDS and his/her family, recognize health care element necessary to copying the to live with HIV. It is a qualitative research by utilizing the Creative and Sensitive Method starting from the development of the Free to Create dynamics, approved by the Ethics Committee in Research of UFRGS CAAE: 14141313.5.0000.5347. The settings to collect information collection were: Non-Governmental Organization and Public Hospital, located in the municipality of Porto Alegre, State of Rio Grande do Sul. The participants were 13 to 20 years-old 18 adolescents and 21 family member/caretaker who were 23 to 71 years of age. The collection of information was carried out from April to July 2013. The research took place upon three moments. First: immersion in productions performed about the theme of the adolescent with HIV/AIDS and his/her family. Second: collection of information with the adolescent and family member/caretaker starting from the development of the dynamics. Third: proposing the elaboration of health care elements for the adolescent who lives with HIV/AIDS and his/her family with the presentation of the results to the participants for possible suggestions. The interpretation of the information was done by Thematic Analysis of the Content. The results were expressed in categories: Adolescence and Sexuality: possibilities of communication spaces with the family member/caretaker and adolescent; practices of self-care and care of the other subject. Treatment and Medication: improvements in the medication presentation. Discrimination: social spaces and means of communication that develop discussions on prevention and discrimination. The disclosure of the diagnosis per person who has bond with the adolescent, mainly the mother or the father, with presence or guidelines from the health service and when inquiries start with questions regarding the disease: human rights and citizenship, duties of the adolescents regarding fulfillment of the treatment, and legal rights – work and benefits for maintaining his/her health. Adolescent and family thinking about discussion in the group, the participants agreed with most of the results pointed out by them, by signaling some of the questions regarding the treatment and the medication, discrimination and human rights and citizenship. In order to transform, to carry out and to strengthen care practices, it is needed the convergence of public policies, education at different levels and assistance. The relevance of the nursing commitment stands out within an interdisciplinary staff, by promoting individual and collective spaces in order to help and to guide the adolescent and the family about health care paths. / Este estudio se inserta en la linea de pesquisa Fundamentos y Prácticas de Enfermería en Salud de la Mujer, niños y Adolescente y está vinculado al Grupo Cuidado a la Salud en las Etapas de la Vida (CEVIDA) del Programa de Pos Grado en Enfermería de la Universidad Federal de Río Grande del Sur (UFRGS). Enfoca las vivencias, llenas de retos oriundos de las demandas de cuidados permanentes con el SIDA, del adolescente, que vive con SIDA/aids, muchas veces tensionado por la fase de la vida. Así, se objetivó: conocer los caminos de cuidado y experiencias del adolescente que vive com SIDA/aids y su familia, identificando elementos de cuidado a la salud necesarios para el afrontamiento del vivir con SIDA. Pesquisa cualitativa, con la utilización del Método Creativo y Sensible desde el deserrollo de la dinámica Libre para Crear, aprobada por el Comité de Ética en Pesquisa de la UFRGS CAAE: 14141313.5.0000.5347. Los escenarios de coleta de informaciones fueron una Organización no Gobernamental (ONG) y un Hospital Público, ubicados en la municipalidad de Porto Alegre, Estado de Río Grande del Sur. Los participantes fueron: 18 adolescentes de 13 a 20 años de edad y 21 familiares/cuidadores de 23 a 71 años de edad. La recopilación de información ocurrió en el período de abril a julio de 2013. La búsqueda ocurrió en tres momentos. Primero: imersión en producciones hechas sobre la temática adolescente que vive con SIDA/aids y familia. Segundo: recopilación de informaciones con adolescente y familiar/cuidador, desde el desarrollo de dinámica. Tercero: propuesta enumerar los elementos de Cuidado a la Salud del adolescente que vive com SIDA/aids y su familia, con la presentación de los resultados a los participantes para posibles sugerencias. Para la interpretación de las informaciones se hizo un Análisis Temático del Contenido. Los resultados fueron expresados en categorías: Adolescencia y Sexualidad: posibilidad de espacios de comunicación con el familiar/cuidador y adolescente, prácticas del cuidado de sí y del otro. Tratamiento y Medicamento: mejoras en la presentación medicamentosa. Discriminación: espacios sociales y medios de comunicación que desarrollen debates de prevención a la discriminación. Divulgación del diagnóstico por persona con vínculo con el adolescente, principalmente madre o padre, con presencia u orientación del servicio de salud y cuando comenzar las preguntas sobre cuestiones relativas a la enfermidad: derechos humanos y ciudadanía, deberes de los adolescentes con el cumplimiento del tratamiento y los derechos legales ― trabajo y beneficios para la manutención de su salud. Elementos del cuidado a la salud del adolescente que vive con SIDA/aids: sugestión del adolescente y familiar/cuidador, los participantes estaban de acuerdo con la mayoría de los resultados apuntados por ellos, siendo sinalizado algunas cuestiones referentes al tratamiento y medicamento, discriminación y derechos humanos y ciudadanía. Para transformar, efectuar y fortalecer las prácticas de cuidado es esencial la convergencia de las políticas públicas, educación en los diferentes niveles y asistencia. Se destaca la relevancia de la participación de la enfermería en equipo interdisciplinario, promoviendo espacios individuales y colectivos para ayudar y guiar al adolescente y familia sobre los caminos de cuidado a la salud.