Análise Da Imunogenicidade De Uma Vacina De DNA Codificando Epitopos CD4 Promíscuos E Conservados Do HIV-1 Em Camundongos BALB

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Análise Da Imunogenicidade De Uma Vacina De DNA Codificando Epitopos CD4 Promíscuos E Conservados Do HIV-1 Em Camundongos BALB SUSAN PEREIRA RIBEIRO Análise da imunogenicidade de uma vacina de DNA codificando epitopos CD4 promíscuos e conservados do HIV-1 em camundongos BALB/c e transgênicos para moléculas de HLA classe II Tese apresentada à Faculdade de Medicina da Universidade de São Paulo para obtenção do título de Doutor em Ciências Programa de: Alergia e Imunopatologia Orientador: Prof. Dr. Edecio Cunha-Neto São Paulo 2010 SUSAN PEREIRA RIBEIRO Análise da imunogenicidade de uma vacina de DNA codificando epitopos CD4 promíscuos e conservados do HIV-1 em camundongos BALB/c e transgênicos para moléculas de HLA classe II Tese apresentada à Faculdade de Medicina da Universidade de São Paulo para obtenção do título de Doutor em Ciências Programa de: Alergia e Imunopatologia Orientador: Prof. Dr. Edecio Cunha-Neto São Paulo 2010 Dados Internacionais de Catalogação na Publicação (CIP) Preparada pela Biblioteca da Faculdade de Medicina da Universidade de São Paulo reprodução autorizada pelo autor Ribeiro, Susan Pereira Análise da imunogenicidade de uma vacina de DNA codificando epitopos CD4 promíscuos e conservados do HIV-1 em camundongos BALC/c e transgênicos para moléculas de HLA classe II / Susan Pereira Ribeiro. -- São Paulo, 2010. Tese(doutorado)--Faculdade de Medicina da Universidade de São Paulo. Programa de Alergia e Imunopatologia. Orientador: Prof. Dr. Edecio Cunha-Neto. Descritores: 1.Vacinas contra HIV 2.Epitopos de linfócito T 3.Linfócitos T CD4-positivos 4.Camundongos transgênicos 5.Diversidade genética 6.Cobertura vacinal 7.Antígenos HLA 8.Vacinas de DNA 9.HIV 10.AIDS USP/FM/DBD-314/10 Eu gostaria de dedicar esta tese aos meus pais, Cláudio e Rosana, aos meus irmãos Daniel, Vivian, Guilherme e Sarah, à minha filha Helena e à minha sobrinha Carolina, pela presença efetiva em cada passo de minha jornada e pela torcida incansável e incessante. AGRADECIMENTOS Gostaria de agradecer Ao Bo pela paciência, carinho e incentivo em cada etapa. À minha querida filha Helena, companheira de todas as horas, pela compreensão nos momentos de ausência e pelo imenso amor. Ao meu orientador Dr Edecio, pelos momentos de discussão científica e por acreditar em mim e em meu trabalho. À minha co-orientadora e grande amiga Dra Daniela, por me acompanhar durante todo esse trajeto, vibrando a cada conquista, pelos puxões de orelha e também pelos momentos de descontração. Ao Dr Jorge Kalil, pelas enriquecedoras reuniões das quintas- feiras. Ao Rafael, nossa nova aquisição laboratorial, que tem acrescentado muito ao grupo como cientista e como amigo. À equipe da UGQ: Candida, Fernanda, Sergio, Issler, Ruth e Neus, pelo enriquecimento que me trouxeram nessa caminhada. Em especial a Candida e a Fernanda pela grande amizade. Aos amigos e colegas de laboratório (LIM60 e LIM19) que direta ou indiretamente contribuíram para o desenvolvimento desse trabalho, proporcionando momentos de discussão científica e também momentos de grande descontração e diversão. À DEUS, minha força maior. Esta tese está de acordo com as seguintes normas, em vigor no momento desta publicação: Referências: Adaptado de Uniform Requirements for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journals Editors (Vancouver). Universidade de São Paulo. Faculdade de Medicina. Serviço de Biblioteca e Documentação. Guia de apresentação de dissertações, teses e monografias. Elaborado por Carneiro da Cunha, A. et al. 2a ed. São Paulo: Serviço de Biblioteca e Documentação; 2005. Abreviaturas dos títulos dos periódicos: List of Journals Indexed in Index Medicus. SUMÁRIO Lista de Abreviaturas, Símbolos e Siglas ......................................... i Lista de Figuras................................................................................... vii Lista de Tabelas................................................................................... ix Lista de Figuras Anexas...................................................................... x Lista de Tabelas Anexas..................................................................... xi Lista de Publicações........................................................................... xii Resumo.................................................................................................. xiii 1. Introdução......................................................................................... 1 1.1. Epidemiologia............................................................................. 3 1.2. Ciclo de vida............................................................................... 4 1.3. Origem do Vírus da Imunodeficiência Humana (HIV)................. 5 1.3.1. Filogenia do HIV-1............................................................... 9 1.4. Tratamento.................................................................................. 9 1.5. Patogênese da infecção pelo HIV-1........................................... 14 1.6. Mecanismos imunológicos de defesa contra o HIV-1................. 20 1.6.1. Resposta imune inata.......................................................... 20 1.6.2. Resposta imune adaptativa................................................. 23 1.7. Vacinas contra o HIV-1............................................................... 25 1.8. Requisitos essenciais a serem induzidos por uma vacina que vise indução de resposta imune celular................................................. 28 1.8.1. Importância de um componente indutor de respostas de + linfócitos T CD4 ..................................................................................... 29 1.8.2. Vacinas baseadas em epitopos........................................... 30 1.8.3. Indução de células polifuncionais........................................ 35 1.8.4. Indução de memória imunológica........................................ 36 2. Objetivos .......................................................................................... 38 2.1. Objetivo geral.............................................................................. 39 2.2. Objetivos específicos.................................................................. 39 3. Métodos............................................................................................. 40 3.1. Síntese automática de peptídeos em fase sólida....................... 41 3.2. Subclonagem do gene multiepitópico artificial codificando epitopos promíscuos e conservados do HIV-1....................................... 42 3.3. Transformação de bactérias DH5 por choque térmico............. 43 3.4. Extração e purificação dos DNAs plasmidiais............................ 44 3.5. Quantificação e avaliação da qualidade dos plasmídeos purificados.............................................................................................. 46 3.6. Animais....................................................................................... 47 3.6.1. Camundongos BALB/c convencionais................................ 47 3.6.2. Camundongos transgênicos para moléculas de HLA classe II................................................................................................... 47 3.7. Imunizações experimentais........................................................ 49 3.7.1. Imunização para avaliação da expressão de RNA.............. 50 3.7.2. Imunização para estabelecimento do protocolo vacinal...... 50 3.7.3. Imunização para avaliação da toxicidade da vacina........... 51 3.7.4. Imunização para avaliação da imunogenicidade................. 51 3.8. Extração de RNA........................................................................ 52 3.8.1. Quantificação de RNA......................................................... 53 3.8.2. Tratamento do RNA total com DNAse I............................... 54 3.8.3. Transcrição reversa............................................................. 54 3.8.4. PCR para GAPDH e PCR para HIVBr18............................. 55 3.9. Suspensão celular...................................................................... 57 3.10. Ensaio de proliferação celular................................................... 57 3.11. Avaliação fenotípica e funcional de linfócitos T........................ 61 3.11.1. Marcação de superfície..................................................... 63 3.11.2. Marcação intracelular........................................................ 63 3.12. Preparo das beads para ajuste das voltagens......................... 65 3.13. ELISPOT para IFN- e IL-2....................................................... 65 3.14. Detecção de citocinas no sobrenadante de cultura através de CBA (Cytometric Bead Array) ................................................................ 66 3.15. ELISA para detecção de Ig Total lldi e IgG............................... 69 4. Resultados........................................................................................ 71 4.1. Construção da vacina................................................................. 72 4.2. Estabelecimento do protocolo vacinal........................................ 75 4.3. Toxicidade da vacina.................................................................. 78 4.4. Avaliação da imunogenicidade da vacina multiepitópica, HIVBr18 em camungongos BALB/c....................................................... 79 4.4.1. Avaliação da resposta imune humoral................................ 90 4.5. Avaliação da longevidade da resposta vacinal........................... 92 4.6. Avaliação da amplitude das respostas induzidas....................... 98 4.7. Avaliação da indução de respostas imunes
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