title: Longitudinal mapping of protective CD4+ T cell responses against HCV: analysis of fluctuating dominant and subdominant HLA-DR11 restricted epitopes.
abstract: 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.
authors.affiliation: Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.
authors.forename: G C
authors.initials: GC
authors.lastname: Harcourt
authors.forename: M
authors.initials: M
authors.lastname: Lucas
authors.forename: I
authors.initials: I
authors.lastname: Sheridan
authors.forename: E
authors.initials: E
authors.lastname: Barnes
authors.forename: R
authors.initials: R
authors.lastname: Phillips
authors.forename: P
authors.initials: P
authors.lastname: Klenerman
mesh_terms: D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004198:Disease Susceptibility; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D059810:HLA-DR Serological Subtypes; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007700:Kinetics; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008875:Middle Aged; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; D016056:Immunodominant Epitopes; D010455:Peptides; D017361:Viral Nonstructural Proteins; C080766:HLA-DR11 antigen; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases