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dc.contributor.authorFitzmaurice, Karen
dc.contributor.authorPetrovic, Danijela
dc.contributor.authorRamamurthy, Narayan
dc.contributor.authorSimmons, Ruth
dc.contributor.authorMerani, Shazma
dc.contributor.authorGaudieri, Silvana
dc.contributor.authorSims, Stuart
dc.contributor.authorDempsey, Eugene
dc.contributor.authorFreitas, Elizabeth
dc.contributor.authorLea, Susan
dc.contributor.authorMcKiernan, Susan
dc.contributor.authorNorris, Suzanne
dc.contributor.authorLong, Aideen
dc.contributor.authorKelleher, Dermot
dc.contributor.authorKlenerman, Paul
dc.date.accessioned2012-02-01T10:45:47Z
dc.date.available2012-02-01T10:45:47Z
dc.date.issued2012-02-01T10:45:47Z
dc.identifier.citationGut. 2011 Nov;60(11):1563-71. Epub 2011 May 6.en_GB
dc.identifier.issn1468-3288 (Electronic)en_GB
dc.identifier.issn0017-5749 (Linking)en_GB
dc.identifier.pmid21551190en_GB
dc.identifier.doi10.1136/gut.2010.228403en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207825
dc.description.abstractBACKGROUND AND AIMS: CD8 T cells are central to the control of hepatitis C virus (HCV) although the key features of a successful CD8 T cell response remain to be defined. In a cohort of Irish women infected by a single source, a strong association between viral clearance and the human lecucocyte (HLA)-A*03 allele has been described, and the aim of this study was to define the protective nature of the associated CD8 T cell response. METHODS: A sequence-led approach was used to identify HLA-A*03-restricted epitopes. We examine the CD8 T cell response associated with this gene and address the likely mechanism underpinning this protective effect in this special cohort, using viral sequencing, T cell assays and analysis of fitness of viral mutants. RESULTS: A strong 'HLA footprint' in a novel NS3 epitope (TVYHGAGTK) was observed. A lysine (K) to arginine (R) substitution at position 9 (K1088R) was seen in a significant number of A*03-positive patients (9/12) compared with the control group (1/33, p=0.0003). Threonine (T) was also substituted with alanine (A) at position 8 (T1087A) more frequently in A*03-positive patients (6/12) compared with controls (2/33, p=0.01), and the double substitution of TK to AR was also observed predominantly in HLA-A*03-positive patients (p=0.004). Epitope-specific CD8 T cell responses were observed in 60% of patients three decades after exposure and the mutants selected in vivo impacted on recognition in vitro. Using HCV replicons matched to the viral sequences, viral fitness was found to be markedly reduced by the K1088R substitution but restored by the second substitution T1087A. CONCLUSIONS: It is proposed that at least part of the protective effect of HLA-A*03 results from targeting of this key epitope in a functional site: the requirement for two mutations to balance fitness and escape provides an initial host advantage. This study highlights the potential protective impact of common HLA-A alleles against persistent viruses, with important implications for HCV vaccine studies.
dc.language.isoengen_GB
dc.subject.meshAdulten_GB
dc.subject.meshAllelesen_GB
dc.subject.meshCD8-Positive T-Lymphocytes/*immunologyen_GB
dc.subject.meshCohort Studiesen_GB
dc.subject.mesh*DNA Footprintingen_GB
dc.subject.meshElectroporationen_GB
dc.subject.meshEpitopes, T-Lymphocyte/chemistry/*immunologyen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshGenetic Fitness/immunologyen_GB
dc.subject.meshHLA-A3 Antigen/genetics/*immunologyen_GB
dc.subject.meshHepatitis C/*immunologyen_GB
dc.subject.meshHumansen_GB
dc.subject.meshImmunodominant Epitopes/immunologyen_GB
dc.subject.meshProtein Biosynthesis/immunologyen_GB
dc.subject.meshSequence Alignmenten_GB
dc.titleMolecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection.en_GB
dc.contributor.departmentDepartment of Clinical Medicine, Trinity College Dublin, St James' Hospital,, Dublin, Ireland. kfitzmau@tcd.ieen_GB
dc.identifier.journalGuten_GB
dc.description.provinceLeinster
html.description.abstractBACKGROUND AND AIMS: CD8 T cells are central to the control of hepatitis C virus (HCV) although the key features of a successful CD8 T cell response remain to be defined. In a cohort of Irish women infected by a single source, a strong association between viral clearance and the human lecucocyte (HLA)-A*03 allele has been described, and the aim of this study was to define the protective nature of the associated CD8 T cell response. METHODS: A sequence-led approach was used to identify HLA-A*03-restricted epitopes. We examine the CD8 T cell response associated with this gene and address the likely mechanism underpinning this protective effect in this special cohort, using viral sequencing, T cell assays and analysis of fitness of viral mutants. RESULTS: A strong 'HLA footprint' in a novel NS3 epitope (TVYHGAGTK) was observed. A lysine (K) to arginine (R) substitution at position 9 (K1088R) was seen in a significant number of A*03-positive patients (9/12) compared with the control group (1/33, p=0.0003). Threonine (T) was also substituted with alanine (A) at position 8 (T1087A) more frequently in A*03-positive patients (6/12) compared with controls (2/33, p=0.01), and the double substitution of TK to AR was also observed predominantly in HLA-A*03-positive patients (p=0.004). Epitope-specific CD8 T cell responses were observed in 60% of patients three decades after exposure and the mutants selected in vivo impacted on recognition in vitro. Using HCV replicons matched to the viral sequences, viral fitness was found to be markedly reduced by the K1088R substitution but restored by the second substitution T1087A. CONCLUSIONS: It is proposed that at least part of the protective effect of HLA-A*03 results from targeting of this key epitope in a functional site: the requirement for two mutations to balance fitness and escape provides an initial host advantage. This study highlights the potential protective impact of common HLA-A alleles against persistent viruses, with important implications for HCV vaccine studies.


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