Adult T-cell leukemia (ATL) is an aggressive lymphoproliferative disorder associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Reactivation of telomerase, a critical event in tumor progression observed in late phases of ATL development, has been shown to be caused by HBZ (HTLV-1 bZIP factor), a regulatory protein encoded by the negative strand of the HTLV-1 genome. The HBZ-mediated up-regulation of the telomerase catalytic subunit is dependent on JunD, which in the cellular context occurs in the complex with menin, the product of the MEN-1 tumor suppressor gene. Interaction with menin represses JunD-dependent transcription and converts JunD into a growth suppressor, whereas it acts as a growth promoter in the absence of menin. My results demonstrate that the viral protein HBZ abrogates tumor suppressor function of menin, resulting in the activation of JunD transcriptional activity and finally in the up-regulation of its target gene, the human telomerase reverse transcriptase (hTERT). I showed that HBZ, JunD and menin can coexist in the same protein complex and that HBZ and menin exert opposite effects on JunD transcriptional activity. Moreover menin inhibits the JunD-mediated activation of the hTERT proximal promoter and HBZ is able to counteract this effect. Finally, I proposed that HBZ, by recruiting p300 histone acetyltransferase, reverses the histone deacetylation conducted by menin-recruited HDACs and therefore up-regulates the expression of the hTERT gene. Altogether, my work led to the identification of the molecular mechanism leading to the functional impairment of the menin tumor suppressor, which results in the deregulation of AP-1 signaling in HTLV-1 infected cells. Finally this work gave new insights into the mechanism of the transcriptional up-regulation of the hTERT gene upon HTLV-1 infection, being a key event during the development of Adult T-cell leukemia and a necessary step towards the progression into more aggressive courses.

Le virus T lymphotropique humain HTLV-1 est l'agent étiologique de la leucémie-lymphome T de l'adulte (ATLL) et de nombreuses maladies inflammatoires. HTLV-1 est associée à de nombreuses modifications quantitatives de l'expression des gènes cellulaires. À ce jour, ces modifications ont été décrites essentiellement à l'échelle transcriptionnelle à travers notamment les effets de l'oncoprotéine virale Tax, et plus récemment HBZ. Outre leurs impacts sur les niveaux d'activité des promoteurs, certains facteurs apparaissent jouer également un rôle dans la régulation de l'épissage alternatif. Ce mécanisme essentiel à la diversité du transcriptome et du protéome cellulaire, apparait étroitement couplé à la transcription et ses dérégulations sont de plus en plus décrites dans les phénomènes cytotoxiques et pathogènes tels que les infections et les cancers. Dans ce contexte, mon travail s'est intéressé à caractériser les profils d'expression des exons des cellules T CD4+ infectées ou non, et transformée ou non par HTLV-1 in vivo. Dans une seconde étude, j'ai abordé les aspects mécanistiques des modifications d'épissage alternatif par HTLV-1. Mes données montrent que, outre ses effets sur la régulation quantitative de l'expression des gènes cellulaires, l'activation de la voie NF-kB par l'oncogène Tax est impliquée dans la reprogrammation de l'épissage alternatif de nombreux gènes. Ces données révèlent un nouveau degré de complexité dans les mécanismes de dérégulation de l'expression des gènes cellulaires par HTLV-1 et ouvre de nouvelles perspectives d'investigations dans la compréhension des processus leucémogènes associés à l'infection par le virus HTLV-1

HTLV-1, un rétrovirus endémique des Antilles-Guyane qui infecte plus de 10 millions de personnes dans le monde, est l’agent étiologique de l’ATL, une leucémie agressive des lymphocytes T CD4+ résistante aux traitements conventionnels actuels. Le rôle émergent des miARN dans la leucémogénèse et la résistance aux chimiothérapies a soulevé des interrogations quant à leurs rôles dans le développement de l’ATL. Les miARN sont de petits ARN non codant qui régulent l’expression génique. Récemment leur altération durant le cycle de vie du HTLV-1 a été mise en lumière. Une des caractéristiques de l’émergence de l’ATL est la perte d’expression des protéines virales codées par le promoteur en amont du génome proviral (LTR5’), à l’exception d’hbz dont l’expression est initiée dans le promoteur en aval du génome proviral (LTR3’). Dans une première étude, nous démontrons, dans un modèle mimant la cellule ATL, qu’HBZ module sa propre transcription à travers une boucle de rétrocontrôle qui implique une coopération avec le facteur de transcription de la famille AP-1 JunD. Nous montrons que l’expression d’HBZ induit des caractéristiques phénotypiques de fibroblastes transformés. Nous avons, ensuite, analysé l’effet d’HBZ sur les miARN dans les cellules ATL et montré qu’il induit une diminution des miARN cellulaires via l’inhibition d’un acteur clé de la maturation, Dicer. En accord avec notre première étude, nous montrons que l’induction d’HBZ dans les CD4+ de patients ATL corrèle avec une augmentation de la charge provirale (CPV) et donc l’évolution de l’ATL. Le traitement de ces cellules au VPA inhibe l’expression d’hbz, restaure celle de dicer et inverse la CPV et donc la prolifération des cellules malignes ex vivo. / HTLV-1, a retrovirus endemic of Antilles-Guyana that infects more than 10 million people worldwide, is the etiological agent of ATL, an aggressive leukemia of CD4+ T lymphocytes resistant in currents treatments. The emerging role of miRNA in leukemogenesis and chemoresistance has risen questioning about their role in ATL development. MiRNAs are a class of non-coding RNAs that regulate gene expression. Involvement of their alteration in the HTLV-1 life cycle has recently come to light. One of the hallmarks of progression toward ATL is the emergence of LTR5’-deficient provirus and thereby eliminating the expression of all viral proteins on the sense strands in these cells, with the exception of the hbz gene regulated by an independent promoter in the 3’LTR. In a first study, using a provirus with the 5’LTR deleted, we found that HBZ modulates its own expression through a positive-feedback loop that involves cooperation with AP-1 transcription factor JunD. We also found that hbz-expressing fibroblasts displayed of a transformed phenotype. Then, we analyzed the effect of HBZ on miRNA expression in ATL patients and report that hbz reduce significantly expression of cellular miRNAs via inhibition of an enzyme essential for maturation, Dicer1. In agreement with our previous study, we show that hbz expression in ATL samples correlates with HTLV-1–provirus load (CPV) and consequently progression of the pathology. VPA treatment of these cells inhibits hbz expression, restores Dicer expression, and inverts the proviral charge thereby reducing cellular proliferation of malignant cells.

Submitted by Hiolanda Rêgo (hiolandarego@gmail.com) on 2015-03-27T11:52:21Z No. of bitstreams: 1 Dissertação_ICS_ Vanessa da Silva Brito.pdf: 1550973 bytes, checksum: a932addd006a46862584dd772338e50a (MD5) / Made available in DSpace on 2015-03-27T11:52:21Z (GMT). No. of bitstreams: 1 Dissertação_ICS_ Vanessa da Silva Brito.pdf: 1550973 bytes, checksum: a932addd006a46862584dd772338e50a (MD5) / Introdução: O vírus linfotrópico de células T humanas tipo 1 (HTLV-1) é um retrovírus linfotrópico, descrito como agente causador da leucemia/linfoma de células T do adulto (ATL) e paraparesia espástica tropical/mielopatia associada ao HTLV-1 (HAM/TSP). Mesmo nos portadores aparentemente assintomáticos existem evidências de comprometimento funcional da resposta imune celular. Os objetivos do presente trabalho foram avaliar as subpopulações linfocitárias e células T regulatórias em indivíduos infectados pelo HTLV-1 e comparar as populações de células T (CD4+, CD8+), por dois kits comerciais diferentes disponíveis. Material e Métodos: Este estudo foi aprovado pelo CEP-207/2009CPqGM/FIOCRUZ. Em amostras de sangue periférico de 55 indivíduos infectados com HTLV-1 (soropositivos) e 80 controles (não infectados / HTLV soronegativos), foram quantificados com os reagentes e kits Lymphogram (Cytognos-Espanha) e Tritest (BD-USA), linfócitos T (CD4+, CD8+, CD25+), células NK e linfócitos B, por reagentes de marcação simultânea, e avaliada a expressão de Foxp3 nas células T CD4+CD25+. Resultado: Com os dados analisados, os indivíduos infectados pelo HTLV-1 apresentam valores mais elevados de células T CD4+ e CD8+, redução na frequência de células NK (p<0,05), sem diferença nas células B, quando comparados aos controles. Observa-se uma menor expressão da proteína Foxp3 em células T CD3+CD4+CD25+ de indivíduos infectados pelo HTLV quando comparados aos não infectados/soronegativos (p<0,05). Discussão: Com base nos resultados, pode-se concluir que o Lymphogram® é um método confiável, rápido e de baixo custo para o diagnóstico e monitoramento de linfopatias como a infecção pelo HTLV-1. Conclusão: As análises quantitativas mostraram que indivíduos infectados pelo HTLV-1 apresentam uma contagem de células T CD4+ e CD8+ maior, mantendo a proporcionalidade nas duas células, e valores menores de células NK, quando comparados aos controles não infectados.

Bien que très proches dans leur organisation génomique, le rétrovirus HTLV-1 est impliqué dans le développement de la leucémie à cellule T de l’adulte (ATL) alors que l’infection par HTLV-2 n’a jamais été associée à des désordres hématologiques malins. La transformation des cellules infectées par HTLV-1 a longtemps été attribuée uniquement à la protéine virale transactivatrice Tax (Tax-1). Cependant, son expression est très faible dans les cellules ATL. La protéine HBZ a été découverte en 2002. Elle est traduite à partir d'un ARNm transcrit à partir du LTR 3' d'HTLV-1 et est exprimée par les cellules infectées issues de tous les patients HTLV-1 quel que soit leur statut clinique. HBZ participe au maintien du phénotype tumoral en stimulant la prolifération des cellules leucémiques et intervient dans l'échappement du virus au système immunitaire. Des analyses in silico nous avaient permis de détecter un cadre ouvert de lecture sur le brin complémentaire de l’ARN génomique d’HTLV-2. Mon travail de thèse a consisté à amplifier et caractériser d’une part le transcrit APH-2 et d’autre part la protéine qui en est issue. Nous avons démontré dans un premier temps que la transcription d’APH-2 était initié dans le LTR 3’ et que le transcrit APH-2 était épissé et poly-adénylé. Nous avons ensuite mis en évidence l’expression d’APH-2 dans les lignées infectées par HTLV-2, ainsi que dans des cultures de lymphocytes issus de deux porteurs sains africains. La mise au point d’une technique quantitative de RT-PCR nous a permis de détecter APH-2 ex vivo chez 94% des individus d’une série de 51 porteurs sains américains. Nous avons aussi montré que l'expression de cet ARNm était proportionnelle à la charge provirale. APH-2 code une protéine de 183 acides aminés dont nous avons mis en évidence l’expression dans la lignée MO. Mes travaux ont aussi permis de démontrer le rôle inhibiteur d’APH-2 sur la transcription virale malgré l’absence d’un domaine bZip classique, ainsi que son interaction avec le facteur de transcription CREB. Par immunofluorescence, nous avons établi la localisation nucléaire d’APH-2. La protéine semble associée aux corps PML grâce à une région de six arginines comprise entre les résidus 78 et 92. Cependant, contrairement à HBZ, nous n’avons pas observé d’interactions entre APH-2 et les facteurs cJun, JunD ou le cofacteur de transcription CBP/p300. De plus nous avons observé qu’APH-2 était incapable d’induire la prolifération des lymphocytes in vitro alors qu’une lymphocytose est souvent observée chez les porteurs d’HTLV-2. Grâce à une approche comparative, mes travaux ont ainsi permis d’apporter des éléments nouveaux dans la compréhension de la différence de pathogénicité qu’il existe entre HTLV-1 et HTLV-2. / Although they are very similar in their genomic organization, the HTLV-1 retrovirus is involved in the development of adult T cell leukaemia (ATL) while HTLV-2 has not been associated to any malignant haematological disorders. The tumoral transformation of infected cells was widely associated to the viral transactivactor protein Tax (Tax-1), which modulates many cellular functions. However, its expression is slightly in ATL cells. In 2002, the HBZ protein was discovered, encoded from the 3’ LTR by the complementary strand of HTLV-1 and expressed by all HTLV-1 infected people. HBZ participates in the maintenance of the tumoral phenotype by stimulating leukemic cells proliferation and is involved in the immune system escape. We recently detected a coding region by an in silico analysis in the complementary strand of HTLV-2. My work consisted in the characterization of the APH-2 transcript, and in a second part, of the associated protein. At first, we characterized the APH-2 transcription initiation in the 3’LTR and that transcript was spliced and poly-adenylated and demonstrated that the APH-2 expression in all HTLV-2 cell lines and in short cultured lymphocytes from African healthy carriers. We used a quantitative RT-PCR on uncultured cells from 51 American HTLV-2 healthy carriers and we we detected APH-2 expression in 94% of them. We then showed that APH-2 RNA expression is correlated to the HTLV-2 proviral load. The APH-2 transcript encoded a 183 amino acid protein that was shown to be expressed in the HTLV-2 infected Mo cell line. Our work demonstrated the inhibitory functions of APH-2 in the viral transcription and its interaction with the transcriptional cofactor CREB despite the lack of a bZip domain. By an immunofluorescence approach we established the nuclear localisation of APH-2, which is in particular in the PML nuclear bodies. We demonstrated that six arginines in the 78-92 amino acids region is involved in this PML colocalization. Contrary to HBZ, we didn’t observe any interaction with between APH-2 and cJun or JunD factors nor with the transcriptional cofactor CBP/p300. Furthermore we showed that APH-2 is not involved in lymphocyte proliferation in vitro although a lymphocytosis is often observed in HTLV-2 carriers. According to this comparative approach, my work allowed us to better understand the difference of pathogenicity existing between HTLV-1 and HTLV-2.

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第19628号 / 医科博第66号 / 新制||医科||5(附属図書館) / 32664 / 京都大学大学院医学研究科医科学専攻 / (主査)教授 髙折 晃史, 教授 浅野 雅秀, 教授 小柳 義夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Embora o vírus linfotrópico de células T humanas do tipo 1 (HTLV-1) seja reconhecido como o agente etiológico da leucemia/linfoma de células T do adulto (ATL) e da paraparesia espástica tropical/mielopatia associada ao HTLV-1 (HAM/TSP), cerca de 90% dos indivíduos infectados permanecem assintomáticos por toda a vida. Até o presente momento, os fatores associados ao desenvolvimento de doença relacionada ao HTLV-1 não foram totalmente elucidados. Sabe-se que o aumento da carga proviral e a expressão de genes virais estão envolvidos no desenvolvimento/progressão de doenças associadas ao HTLV-1. Assim, por exemplo, a proteína Tax modula genes envolvidos na patogênese da HAM/TSP e genes regulados por HBZ estimulam a proliferação de linfócitos T, induzindo a ATL. Desde a última década, diversos estudos têm demonstrado que células transformadas pelo HTLV-1 apresentam microRNAs do hospedeiro desregulados, o que poderia promover alteração na expressão de genes virais (tax e HBZ), com possível contribuição para o desenvolvimento de HAM/TSP e ATL. Diante desses indícios, o presente estudo teve como objetivos: i) quantificar a expressão de miRNAs humanos conhecidos em células T CD4+ e T CD8+ do sangue periférico de indivíduos assintomáticos infectados por HTLV-1 e de pacientes com HAM/TSP; ii) identificar padrões diferenciais de expressão de miRNAs desregulados que pudessem caracterizar os grupos de pacientes de acordo com sua condição clínica; iii) investigar associações dos padrões diferenciais de expressão de miRNAs com a carga proviral e com a expressão dos genes tax e HBZ de HTLV-1. Analisou-se o perfil de expressão de 754 miRNAs em células T CD4+ e TCD8+ infectadas por HTLV-1 em 19 indivíduos assintomáticos, 17 pacientes com HAM/TSP e 14 controles não infectados. Foram detectados 10 miRNAs diferencialmente expressos no grupo HAM, quando comparados ao grupo ASS (super-expressos: hsa-miR-133a, -148a, -211, -330, -369-5p, -486 e -889 e sub-expressos: hsa-miR-520b, -520e e -566). A expressão alterada dos hsa-miR-133a, -148a, -211, e -889 (super-expressos) e do hsa-miR-520b (sub-expresso) foi correlacionada à carga proviral e a do hsa-miR-211 (super-expresso) à expressão de tax. Além disso, ao analisar as vias canônicas geradas no estudo, identificaram-se as moléculas IL6ST, PTPN11, MAP2K5, ELK4, AKT1, BAD, FOSL1, IRAK 3, CDC42, STAT3 e CREB A como potencialmente afetadas pela expressão alterada de miRNAs no grupo HAM, quando comparado com o grupo ASS. Tais achados mostram-se úteis para o delineamento futuro de estudos longitudinais com indivíduos infectados por HTLV-1, com vistas à identificação de biomarcadores prognósticos de risco para o desenvolvimento de HAM/TSP. / Even though human lymphotropic virus type 1 (HTLV-1) is etiologically linked to adult T-cell leukemia (ATL) and to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), about 90% of infected individuals remain asymptomatic lifelong. So far, factors that are associated with development of HTLV-1-related disease have not been totally clarified. Increase in proviral load and expression of viral genes are recognized as involved in disease development and progression. For instance, the Tax protein is known to modulate genes that are involved in HAM/TSP pathogenesis and HBZ-regulated genes account for T lymphocyte proliferation that leads to ATL. In the last decade, several studies have shown that HTLV-1-transformed cells exhibit dysregulated human microRNA expression, which could result in altered viral gene expression (tax and HBZ), contributing to the development of HAM/TSP and ATL. Based on this evidence, our study aimed at: i) quantifying known human miRNA expression in CD4+ and CD8+ peripheral blood T-cells from HTLV-1 asymptomatic carriers and patients with HAM/TSP; ii) identifying distinctive dysregulated miRNA expression profiles that could distinguish patients according to their clinical status; iii) investigating associations between differential miRNA expression profiles with proviral load and with HTLV-1 tax and HBZ gene expression. We analysed the expression profile of 754 miRNAs in CD4+ e CD8+ peripheral blood T cells from 19 HTLV-1 asymptomatic carriers (AC), 17 patients with HAM/TSP (HAM) and in 14 non-infected controls. Ten differentially expressed miRNAs were found in HAM, as compared with AC (overexpressed: hsa-miR-133a, -148a, -211, -330, -369-5p, -486 and -889; and underexpressed: hsa-miR-520b, -520e and -566). Altered expression of hsa-miR-133a, -148a, -211, and -889 (overexpressed) and of hsa-miR-520b (underexpressed) was shown to be correlated with proviral load and that of hsa-miR-211 (overexpressed) with tax expression. Moreover, analysing the miRNA canonical pathways generated in this study, we identified IL6ST, PTPN11, MAP2K5, ELK4, AKT1, BAD, FOSL1, IRAK 3, CDC42, STAT3 and CREB A as molecules that are potentially affected by altered miRNA expression in HAM, as compared to AC. Our findings are useful for the future design of longitudinal studies of HTLV-1 infected cohorts, aiming at the recognition of prognostic biomarkers of risk for the development of HAM/TSP

Embora o vírus linfotrópico de células T humanas do tipo 1 (HTLV-1) seja reconhecido como o agente etiológico da leucemia/linfoma de células T do adulto (ATL) e da paraparesia espástica tropical/mielopatia associada ao HTLV-1 (HAM/TSP), cerca de 90% dos indivíduos infectados permanecem assintomáticos por toda a vida. Até o presente momento, os fatores associados ao desenvolvimento de doença relacionada ao HTLV-1 não foram totalmente elucidados. Sabe-se que o aumento da carga proviral e a expressão de genes virais estão envolvidos no desenvolvimento/progressão de doenças associadas ao HTLV-1. Assim, por exemplo, a proteína Tax modula genes envolvidos na patogênese da HAM/TSP e genes regulados por HBZ estimulam a proliferação de linfócitos T, induzindo a ATL. Desde a última década, diversos estudos têm demonstrado que células transformadas pelo HTLV-1 apresentam microRNAs do hospedeiro desregulados, o que poderia promover alteração na expressão de genes virais (tax e HBZ), com possível contribuição para o desenvolvimento de HAM/TSP e ATL. Diante desses indícios, o presente estudo teve como objetivos: i) quantificar a expressão de miRNAs humanos conhecidos em células T CD4+ e T CD8+ do sangue periférico de indivíduos assintomáticos infectados por HTLV-1 e de pacientes com HAM/TSP; ii) identificar padrões diferenciais de expressão de miRNAs desregulados que pudessem caracterizar os grupos de pacientes de acordo com sua condição clínica; iii) investigar associações dos padrões diferenciais de expressão de miRNAs com a carga proviral e com a expressão dos genes tax e HBZ de HTLV-1. Analisou-se o perfil de expressão de 754 miRNAs em células T CD4+ e TCD8+ infectadas por HTLV-1 em 19 indivíduos assintomáticos, 17 pacientes com HAM/TSP e 14 controles não infectados. Foram detectados 10 miRNAs diferencialmente expressos no grupo HAM, quando comparados ao grupo ASS (super-expressos: hsa-miR-133a, -148a, -211, -330, -369-5p, -486 e -889 e sub-expressos: hsa-miR-520b, -520e e -566). A expressão alterada dos hsa-miR-133a, -148a, -211, e -889 (super-expressos) e do hsa-miR-520b (sub-expresso) foi correlacionada à carga proviral e a do hsa-miR-211 (super-expresso) à expressão de tax. Além disso, ao analisar as vias canônicas geradas no estudo, identificaram-se as moléculas IL6ST, PTPN11, MAP2K5, ELK4, AKT1, BAD, FOSL1, IRAK 3, CDC42, STAT3 e CREB A como potencialmente afetadas pela expressão alterada de miRNAs no grupo HAM, quando comparado com o grupo ASS. Tais achados mostram-se úteis para o delineamento futuro de estudos longitudinais com indivíduos infectados por HTLV-1, com vistas à identificação de biomarcadores prognósticos de risco para o desenvolvimento de HAM/TSP. / Even though human lymphotropic virus type 1 (HTLV-1) is etiologically linked to adult T-cell leukemia (ATL) and to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), about 90% of infected individuals remain asymptomatic lifelong. So far, factors that are associated with development of HTLV-1-related disease have not been totally clarified. Increase in proviral load and expression of viral genes are recognized as involved in disease development and progression. For instance, the Tax protein is known to modulate genes that are involved in HAM/TSP pathogenesis and HBZ-regulated genes account for T lymphocyte proliferation that leads to ATL. In the last decade, several studies have shown that HTLV-1-transformed cells exhibit dysregulated human microRNA expression, which could result in altered viral gene expression (tax and HBZ), contributing to the development of HAM/TSP and ATL. Based on this evidence, our study aimed at: i) quantifying known human miRNA expression in CD4+ and CD8+ peripheral blood T-cells from HTLV-1 asymptomatic carriers and patients with HAM/TSP; ii) identifying distinctive dysregulated miRNA expression profiles that could distinguish patients according to their clinical status; iii) investigating associations between differential miRNA expression profiles with proviral load and with HTLV-1 tax and HBZ gene expression. We analysed the expression profile of 754 miRNAs in CD4+ e CD8+ peripheral blood T cells from 19 HTLV-1 asymptomatic carriers (AC), 17 patients with HAM/TSP (HAM) and in 14 non-infected controls. Ten differentially expressed miRNAs were found in HAM, as compared with AC (overexpressed: hsa-miR-133a, -148a, -211, -330, -369-5p, -486 and -889; and underexpressed: hsa-miR-520b, -520e and -566). Altered expression of hsa-miR-133a, -148a, -211, and -889 (overexpressed) and of hsa-miR-520b (underexpressed) was shown to be correlated with proviral load and that of hsa-miR-211 (overexpressed) with tax expression. Moreover, analysing the miRNA canonical pathways generated in this study, we identified IL6ST, PTPN11, MAP2K5, ELK4, AKT1, BAD, FOSL1, IRAK 3, CDC42, STAT3 and CREB A as molecules that are potentially affected by altered miRNA expression in HAM, as compared to AC. Our findings are useful for the future design of longitudinal studies of HTLV-1 infected cohorts, aiming at the recognition of prognostic biomarkers of risk for the development of HAM/TSP

Submitted by Cássio da Cruz Nogueira (cassionogueirakk@gmail.com) on 2017-10-17T12:31:32Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_PrevalenciaSintomasUrinarios.pdf: 1491704 bytes, checksum: f7067ef3fc571e872068dcb65c7d4bf9 (MD5) / Approved for entry into archive by Irvana Coutinho (irvana@ufpa.br) on 2017-10-24T14:57:15Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_PrevalenciaSintomasUrinarios.pdf: 1491704 bytes, checksum: f7067ef3fc571e872068dcb65c7d4bf9 (MD5) / Made available in DSpace on 2017-10-24T14:57:16Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_PrevalenciaSintomasUrinarios.pdf: 1491704 bytes, checksum: f7067ef3fc571e872068dcb65c7d4bf9 (MD5) Previous issue date: 2014 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O vírus linfotrópico de células T humanas do tipo 1 (HTLV-1) infecta cerca de 20 milhões de pessoas em todo mundo. Ele está associado principalmente à leucemia/linfoma de células T do adulto (LLTA) e à doença neurológica paraparesia espástica tropical/mielopatia associada ao HTLV (PET/MAH). A PET/MAH provoca alterações motoras, fraqueza, rigidez nos membros inferiores, disfunções erétil e urinária. Alguns estudos demonstram que existe uma tendência de pacientes portadores de HTLV-1 apresentarem algum sintoma urinário não apenas em indivíduos com PET/MAH, mas também em indivíduos considerados como portadores assintomáticos, destacando a importância de estudos que abordem o universo dos sintomas urinários em indivíduos portadores de HTLV-1 a fim de aprofundar o conhecimento científico da evolução clínica dos indivíduos infectados pelo vírus, favorecer diagnósticos e intervenções mais precoces e melhorar a qualidade de vida e a saúde dos portadores de HTLV-1. A presente pesquisa teve por objetivo principal verificar a prevalência de sintomas urinários entre indivíduos portadores de HTLV-1 e, como objetivos específicos, descrever as características sócio-demográficas; identificar os sintomas urinários mais frequentes; verificar a associação da presença de sintomas urinários aos achados clínico-neurológicos e analisar o impacto na qualidade de vida dos sintomas urinários em indivíduos portadores de HTLV-1. Foi realizado um estudo transversal envolvendo 45 indivíduos portadores de HTLV-1 atendidos no ambulatório do NMT⁄UFPA, por meio de avaliação clínico-neurológica, avaliação quanto à presença de sintomas urinários e avaliação do impacto dos sintomas urinários sobre a qualidade de vida com a aplicação do King´s Health Questionnaire. A amostra apresentou média de 48,82 anos de idade, sendo a maioria assintomática (64,44%); do gênero feminino (64,44%); casada (64,44%), com ensino fundamental (53,33%); sem conhecimento do seu modo de infecção (53,33%). A prevalência de sintomas urinários foi de 73,33% sendo 69% entre portadores de HTVL-1 assintomáticos e 81,3% entre indivíduos com PET⁄MAH. Os sintomas urinários mais frequentes foram a noctúria (71,11%); urge-incontinência (44,44%) e urgência urinária (42,22%). Não houve associação entre os achados clínico-neurológicos e a presença de sintomas urinários e, a avaliação da qualidade de vida mostrou impacto negativo em sete dos nove domínios abordados pelo questionário. Foi encontrada alta prevalência de sintomas urinários em indivíduos portadores de HLTV-1, não somente em indivíduos com PET⁄MAH, mas também em portadores considerados assintomáticos. Sugere-a realização de novos estudos com amostras maiores e com exames de diagnóstico mais precisos para esclarecer melhor o surgimento desses sintomas entre os portadores assintomáticos do HTLV-1 e sua relação com o agravamento da mielopatia. / The human T-cells lymphotropic virus type 1 (HTLV-I) infects approximately 20 million people worldwide. It is mainly associated with adult T-cell leukemia/lymphoma (ATLL) and a neurological disease HLTV associated myelopathy/ tropical spastic paraparesis (HAM/TSP). The HAM/TSP causes motor abnormalities, weakness, increased tone in the lower limbs, urinary and erectile dysfunction. Studies show that there is a tendency of patients with HTLV-I to have some urinary symptoms. These symptoms persist not only in individuals with HAM/TSP, but also in individuals considered as asymptomatic carriers. This highlights the importance of studies that address the multitude of urinary symptoms in individuals with HTLV-I in order to deepen the scientific knowledge of the clinical progression of HTLV-I infected individuals, facilitate diagnosis, allow for earlier interventions and improve the quality of life and health of patients with HTLV-I. This research was aimed to determine the prevalence of urinary symptoms among individuals with HTLV-I with the specific objectives to describe the socio-demographic characteristics; identify the most frequent urinary symptoms reported; verify the association of the presence of urinary symptoms to neurological findings and analyze the impact on quality of life of urinary symptoms in individuals with HTLV-I. The study involved cross-sectional analysis involving 45 individuals with HTLV-I through the outpatient clinic at the NMT/UFPA. Through clinical neurological evaluation, the presence of urinary symptoms and impact assessment of urinary symptoms on quality of life by carriers HTLV-I was assessed applying the King's Health Questionnaire. The sample have had an average of 48.82 years of age, most were asymptomatic (64,44%), female (64,44%), married (64,44%), with primary education (53,33%) and without knowledge of its mode of infection (53,33%). The prevalence of urinary symptoms was 73,33% being 69% among patients with asymptomatic HTVL-I and 81,3% among individuals with HAM/TSP. The most common urinary symptoms were nocturia (71.11%), urinary urgency with incontinence (44.44%) and urinary urgency (42.22%). There was no association between neurological findings and the presence of urinary symptoms and the assessment of quality of life showed negative impact on seven of the nine areas covered by the questionnaire. High prevalence of urinary symptoms was found in individuals with HTLV-I, not only in individuals with HAM/TSP, but also in patients considered asymptomatic carriers. It is suggested that further studies with larger sample sizes and more accurate diagnostic tests to clarify development of these symptoms among asymptomatic carriers and its relationship with the worsening of myelopathy.