BACKGROUND/AIMS: A vigorous T-cell response is essential for the resolution of HCV infection. It is modified by co-stimulatory molecules that attenuate T-lymphocyte responses by binding to CTLA4. We investigated whether CTLA4 single nucleotide polymorphisms are associated with the resolution of infection or with the course of disease. METHODS: We enrolled 127 individuals with self-limited and 947 patients with chronic HCV infection, of whom 560 were treated with interferon-alpha-based therapies, and 200 healthy controls. We analyzed CTLA4 polymorphisms -318C>T and +49A>G by melting curve analysis and reconstructed haplotypes. RESULTS: CTLA4 haplotypes were distributed differently between men but not women with self-limited and chronic infection (p=0.043) but were not predictive of the stage of fibrosis in chronic carriers. Haplotypes were distributed differently between male but not female end-of-treatment responders and non-responders (p=0.025). The influence of CTLA4 haplotypes was more pronounced in "hard-to-treat" situations, i.e., treatment with interferon-alpha monotherapy or infection with HCV genotypes 1/4. Logistic regression analysis confirmed gender-specific risk factors for a virological non-response. CONCLUSIONS: CTLA4 polymorphisms are associated with the resolution of HCV infection. This study underlines the role of an efficient T-cell response in the clearance of HCV and sheds light on a gender-dependent difference of immune regulation.
BACKGROUND/AIMS: A vigorous T-cell response is essential for the resolution of HCV infection. It is modified by co-stimulatory molecules that attenuate T-lymphocyte responses by binding to CTLA4. We investigated whether CTLA4 single nucleotide polymorphisms are associated with the resolution of infection or with the course of disease. METHODS: We enrolled 127 individuals with self-limited and 947 patients with chronic HCV infection, of whom 560 were treated with interferon-alpha-based therapies, and 200 healthy controls. We analyzed CTLA4 polymorphisms -318C>T and +49A>G by melting curve analysis and reconstructed haplotypes. RESULTS:CTLA4 haplotypes were distributed differently between men but not women with self-limited and chronic infection (p=0.043) but were not predictive of the stage of fibrosis in chronic carriers. Haplotypes were distributed differently between male but not female end-of-treatment responders and non-responders (p=0.025). The influence of CTLA4 haplotypes was more pronounced in "hard-to-treat" situations, i.e., treatment with interferon-alpha monotherapy or infection with HCV genotypes 1/4. Logistic regression analysis confirmed gender-specific risk factors for a virological non-response. CONCLUSIONS:CTLA4 polymorphisms are associated with the resolution of HCV infection. This study underlines the role of an efficient T-cell response in the clearance of HCV and sheds light on a gender-dependent difference of immune regulation.
Authors: Fernando H Wolff; Sandra C Fuchs; Nêmora N T Barcellos; Paulo Ricardo de Alencastro; Maria Letícia R Ikeda; Ajácio B M Brandão; Maicon Falavigna; Flávio D Fuchs Journal: PLoS One Date: 2010-05-05 Impact factor: 3.240