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2.
Hepatology ; 48(3): 713-22, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18712791

ABSTRACT

UNLABELLED: Both strong antigenic avidity and acquisition of proper effector functions contribute to the efficacy of antiviral T cell responses. To correlate these parameters with the outcome of hepatitis C virus (HCV) infection, we characterized HCV-specific CD8 T cell lines isolated after immunomagnetic sorting of peripheral blood mononuclear cells from human leukocyte antigen A*02 (HLA-A*02) individuals with various HCV serological statuses, using recombinant HLA-A*0201 multimers loaded with three immunodominant HCV genotype 1-derived epitopes. CD8 T cells specific for these three epitopes were derived from most HLA-A*0201 individuals, regardless of their HCV serology or clinical outcome. Donors recovered from genotype 1 HCV infection were enriched for high-avidity T cells with enhanced interferon gamma (IFN-gamma), tumor necrosis factor alpha, and cytotoxic T lymphocyte responses, when compared with seronegative donors and seropositive patients infected with irrelevant HCV genotypes. Patients chronically infected with genotype 1 strain yielded almost exclusively low-avidity T cells, whose hyporesponsiveness was primarily attributable to low T cell receptor (TCR) avidity rather than intrinsic functional defects. CONCLUSION: This study suggests that strong IFN-gamma responses associated with efficient viral clearance primarily result from Ag-driven selection/survival of HCV-specific T cells expressing high-avidity TCR. It also suggests a link between the quality of the initial HCV-specific T cell repertoire and susceptibility to chronic infection.


Subject(s)
Antibody Affinity/immunology , CD8-Positive T-Lymphocytes/immunology , Hepatitis C/immunology , Immunity, Cellular/physiology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Case-Control Studies , Cell Line , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , Genotype , HLA-A Antigens/genetics , HLA-A Antigens/immunology , HLA-A2 Antigen , Hepacivirus/immunology , Hepatitis C/metabolism , Hepatitis C/pathology , Humans , Interferon-gamma/metabolism , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Cytotoxic/pathology , Tumor Necrosis Factor-alpha/metabolism
3.
J Clin Microbiol ; 44(10): 3600-7, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17021089

ABSTRACT

A national evaluation study was performed in 14 specialized laboratories with the objective of assessing their capacities to provide (i) hepatitis B virus (HBV) viral loads (VL), (ii) HBV genotypes, and(iii) identification of precore/core mutants. The panel consisted of 12 HBV DNA-positive samples with VLs from 2.8 to 9.1 log(10) copies/ml, different HBV genotypes (A to F), and 3 mutant and 9 wild-type samples at nucleotide 1896. The coefficients of variation of the mean VLs ranged from 2.4% to 10.4% with the Cobas HBV Monitor assay, from 1.8% to 5.5% with the Cobas TaqMan 48, from 1.5 to 26.2% with RealArt HBV PCR, and from 0 to 7% with branched DNA (bDNA). The Cobas Monitor assay underestimated the VLs of genotype F samples, with differences ranging from 1.4 to 2.4 log(10) copies/ml. The accuracies of genotype determinations ranged from 33% to 100%, and those of precore mutant determinations ranged from 25 to 100%. This study showed some drawbacks of two widely used assays: (i) Cobas Monitor has a narrow dynamic range and underestimates genotype F sample VLs and (ii) bDNA shows poor sensitivity and may fail to identify patients with low VLs. With higher performance in terms of analytical sensitivity combined with a larger dynamic range and an ability to quantify the main genotypes equally, real-time PCR methods appear more appropriate for accurate monitoring of HBV DNA quantification. Furthermore, the clinical implications of HBV genotyping and the determination of precore/core mutants need to be clearly stated to justify the standardization of these methods.


Subject(s)
Hepatitis B virus/genetics , Hepatitis B virus/isolation & purification , Hepatitis B/virology , Laboratories/standards , Viral Core Proteins/genetics , Viral Load , France , Genotype , Humans , Multicenter Studies as Topic/standards , Mutation
5.
J Virol ; 76(18): 9516-25, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12186933

ABSTRACT

Hepatitis A virus (HAV) is a positive-stranded RNA virus in the genus Hepatovirus in the family Picornaviridae So far, analysis of the genetic variability of HAV has been based on two discrete regions, the VP1/2A junction and the VP1 N terminus. In this report, we determined the nucleotide and deduced amino acid sequences of the complete VP1 gene of 81 strains from France, Kosovo, Mexico, Argentina, Chile, and Uruguay and compared them with the sequences of seven strains of HAV isolated elsewhere. Overall strain variation in the complete VP1 gene was found to be as high as 23.7% at the nucleotide level and 10.5% at the amino acid level. Different phylogenetic methods revealed that HAV sequences form five distinct and well-supported genetic lineages. Within these lineages, HAV sequences clustered by geographical origin only for European strains. The analysis of the complete VP1 gene allowed insight into the mode of evolution of HAV and revealed the emergence of a novel variant with a 15-amino-acid deletion located on the VP1 region where neutralization escape mutations were found. This could be the first antigenic variant of HAV so far identified.


Subject(s)
Disease Outbreaks , Evolution, Molecular , Hepatitis A virus/classification , Hepatitis A virus/genetics , Hepatitis A/epidemiology , Viral Structural Proteins/genetics , Amino Acid Sequence , France/epidemiology , Genetic Variation , Hepatitis A/virology , Humans , Mexico/epidemiology , Molecular Sequence Data , Phylogeny , Picornaviridae/genetics , Sequence Analysis, DNA , South America/epidemiology , Yugoslavia/epidemiology
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