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Cellular immunity plays an important role in the control of persistent virus infections such as hepatitis C virus (HCV). Antiviral CD4(+) T cell responses have been shown to accompany resolution of acute disease and there is also a consistent association between HLA Class II genes, notably HLADRB1*1101 (and the closely linked HLADQB1*0301) and disease resolution. We initially mapped longitudinal CD4(+) T cell responses in an individual after spontaneous resolution of acute HCV, and identified three HLA-DR11-restricted responses which vary in immunodominance over time. Functional assays and HLA Class II tetramer staining revealed one to be a response to a commonly recognized epitope, NS3(1248-1261), although cytokine capture assays showed these specific cells to be at a very low frequency. In this patient, and in others reported, this most frequently recognized HLA-DR11 restricted epitope is not immunodominant. We analysed whether sequence variability within and between genotypes might account for differences in recognition of HLA-DR11 restricted epitopes. We found that a limited number, including NS3(1248-1261), showed extreme sequence conservation. Within NS3, the ability of peptides to accept amino acid substitutions was clearly related to the structure of the protein. Overall the data provide a deeper understanding of the relationship between protein structure and variability of HLA-DR11 restricted peptides and may explain the apparent dominance of responses to NS3(1248-1261) across studies but not within an individual immune response.

Original publication

DOI

10.1111/j.1365-2893.2004.00516.x

Type

Journal article

Journal

J Viral Hepat

Publication Date

07/2004

Volume

11

Pages

324 - 331

Keywords

Antigens, Viral, CD4-Positive T-Lymphocytes, Cells, Cultured, Disease Susceptibility, Epitopes, T-Lymphocyte, HLA-DR Antigens, HLA-DR Serological Subtypes, Hepacivirus, Hepatitis C, Humans, Immunodominant Epitopes, Kinetics, Lymphocyte Activation, Lymphocyte Count, Middle Aged, Models, Molecular, Peptides, Viral Nonstructural Proteins