A genotipagem dos SNPs foi realizada através de sondas alelo específicas fluorescentes (TaqMan®, Life), utilizando os seguintes ensaios: C_8921230_20 (rs1800692), C_2298465_20 (rs767455), C_7514879_10 (rs1800629), C_7701116_10 (rs2230926) e C_145670_10 (rs8904). Os ensaios foram preparados conforme recomendações do fabricante. As amostras foram corridas utilizando a plataforma para PCR em tempo real ABI-7500 (Life Technologies).
3.5 Análises Estatísticas
Após a genotipagem de ambos os grupos controle e caso, foram calculadas as frequências alélicas e genotípicas, por contagem direta. Para avaliar o equilíbrio de Hardy-Weinberg e as
possíveis associações foram utilizados, respectivamente, o Teste Qui-quadrado e o Teste Exato de Fisher utilizando o pacote SNPassoc (GONZÁLEZ et al., 2007) disponível no programa R (http://www.r-project.org). Também utilizando as ferramentas do R, foram calculadas a Odds Ratio (OR) e o intervalo de confiança para 95% (IC95%). Em todas as análises, p-values < 0.05 foram considerados estatisticamente significantes.
O desequilíbrio de ligação e a formação de possíveis blocos haplotípicos e/ou combinação de alelos foram verificados através do programa Haploview versão 4.2 (BARRETT et al., 2005) e pelo SNPstats (SOLÉ et al., 2006).
Adicionalmente, foi calculado o poder do estudo por meio do programa G*power versão 3.1(FAUL et al., 2007)
4 RESULTADOS
Todos os resultados obtidos no presente trabalho estão detalhados em forma de artigo (Apêndice A)
5 CONSIDERAÇÕES FINAIS
Apesar do processo apoptótico ser o principal mecanismo envolvido na depleção de LT CD4+, conduzindo a falha imunológica, a presença de SNPs em genes da via do TNF-α/TNFR1, estudados no presente trabalho, não se mostraram associados à resposta a TARV. Havendo assim, a necessidade de novos estudos com maior número de indivíduos e com a adição de novos genes da via e um maior número de SNPs, visando esclarecer o real papel dessas variações no processo de falha imunológica em indivíduos com uso regular de TARV.
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APÊNDICE A
Polimorfismos de base única em genes da via TNF-α/TNFR1 e a resposta ao tratamento antirretroviral na infecção pelo vírus HIV-1
Maria Leonilda Gondim Silvaa,b, Ronaldo Celerino da Silvab, Antonio Victor Campos Coelhob,c, Paulo Sérgio Ramos de Araújod, Neyla Maria Pereira Alvesb , Lucas André Cavalcanti Brandãoa,b*
aDepartamento de Patologia, Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.
bLaboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco,Recife, Pernambuco, Brasil
cDepartmento de Genética, Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil. dHospital das Clinícas (HC-UFPE), Universidade Federal de Pernambuco, Recife, Pernambuco, Brasil.
*Autor Correspondente:
Dr. Lucas André Cavalcanti Brandão
Departamento de Patologia – Universidade Federal de Pernambuco
Av. Prof. Moraes Rego, S/N, Cidade Universitária. CEP: 50670-901. Recife, Pernambuco, Brasil. Telefone: +55 8121268484 e fax: +55 8121268485.
E-mail: lucabrand@gmail.com
Resumo
A infecção pelo Vírus da Imunodeficiência Humana 1 (HIV-1) tem como característica clássica a depleção de linfócitos T (LT) CD4+, que quando não tratada culmina na Síndrome da Imunodeficiência Adquirida (AIDS). Com o advento da Terapia Antirretroviral (TARV), observou-se uma verdadeira revolução. A TARV, apesar de não eliminar o vírus, consegue manter a carga viral em níveis indetectáveis, melhorando a qualidade de vida dos indivíduos infectados. No entanto, 15-30% dos indivíduos em uso regular de TARV e com carga viral indetectável não conseguem recuperar os níveis de LT CD4+ (Recuperação Imunológica).
Estudos apontam que a apoptose está envolvida na depleção dos LT CD4+ e que variações genéticas como polimorfismos de base única (SNPs) em moléculas envolvidas nas vias da apoptose podem levar a diferentes respostas imunológicas do indivíduo à infecção. Neste sentido, o presente estudo se objetiva em investigar o papel de SNPs (rs1800692, rs767455, rs2270926, rs8904, rs1800629) em genes codificadores de proteínas que ativam a via extrínseca da apoptose, através do TNF-α/TNFR1, e sua relação com a recuperação imunológica de pacientes com uso regular de TARV. Foram estudados 113 pacientes HIV positivos, atendidos e tratados no Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), em uso de TARV por um ano e com carga viral indetectável, os quais foram divididos em dois grupos: sucesso imunológico (controle) e falha imunológica (caso). Não foram observadas associações entre os polimorfismos dos genes estudados com o sucesso ou a falha imunológica apresentada pelos indivíduos fazendo uso regular da TARV. Também não foi observada nenhuma associação entre a falha com as variáveis clínicas: peso, etnia, idade, gênero e esquema terapêutico. Apesar da ausência de associações dos SNPs estudados com a falha imunológica, alguns fatores limitantes do estudo devem ser considerados (pequeno número amostral, não inclusão de outras moléculas da via estudada), havendo necessidade de novos estudos de réplica em outras populações.
Palavras-chave: Apoptose, SNPs, TNF-α/TNFR1, HIV, TARV.
Introdução
O Vírus da Imunodeficiência Humana (HIV) infecta majoritariamente linfócitos T CD4+
do hospedeiro (WILEN; TILTON; DOMS, 2012), levando a uma profunda depleção deste tipo celular, resultando no surgimento de doenças definidoras da Síndrome da Imunodeficiência Adquirida (AIDS) (PAIARDINI; MÜLLER-TRUTWIN, 2013). Indivíduos infectados apresentam ativação imune crônica e um padrão inflamatório desde a fase aguda da infecção. A ativação imune crônica, juntamente com a perda continuada dos linfócitos T CD4+ leva o indivíduo ao estado de exaustão imune, incapacitando as células do sistema imune em responder de forma eficiente a infecção pelo HIV e outros patógenos. Assim, a contagem de LT CD4+ é tida como um determinante para progressão da doença (GONZALEZ; ZAPATA; RUGELES, 2016).
Com o advento da Terapia Antirretroviral (TARV), na década de 80, foi observado um grande avanço na luta contra a infecção. Mesmo não eliminando o vírus, a TARV, após uso regular por três meses, reduz significativamente a carga viral a níveis indetectáveis e incrementa os níveis de LT CD4+. Cerca de 80% dos indivíduos conseguem alcançar o sucesso virológico (carga viral plasmática inferior a 50 cópias/mL). No entanto existe um grupo de indivíduos que não consegue recuperar os níveis de LT CD4+, mesmo apresentando carga viral indetectável. Esses pacientes são conhecidos como pacientes em falha imunológica (COHEN et al., 2011).