ArticleGut2011
Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection.
Article in Gut, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed.
- A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory.Science translational medicine · 2014Trial
- The development of a pan-genotypic T cell vaccine against hepatitis C virus using heterologous prime-boost strategies.Hepatology (Baltimore, Md.) · 2026Article
- Targets of protective immunity and opportunities in hepatitis C virus vaccine development.Nature reviews. Immunology · 2026Review
- Joint host-pathogen genomic analysis identifies hepatitis B virus mutations associated with human NTCP and HLA class I variation.American journal of human genetics · 2024Article
- Contemporary Insights into Hepatitis C Virus: A Comprehensive Review.Microorganisms · 2024Review
- T-Cell Exhaustion in HIV-1/Hepatitis C Virus Coinfection Is Reduced After Successful Treatment of Chronic Hepatitis C.Open forum infectious diseases · 2023Article
- Review
- Uncovering Resistance to Hepatitis C Virus Infection: Scientific Contributions and Unanswered Questions in the Irish Anti-D Cohort.Pathogens (Basel, Switzerland) · 2022Review
- CD8Frontiers in immunology · 2022Article
- Review
- Review
- T-Cell Immunity against the Hepatitis C Virus: A Persistent Research Priority in an Era of Highly Effective Therapy.Cold Spring Harbor perspectives in medicine · 2021Review
- Generation of a Novel SARS-CoV-2 Sub-genomic RNA Due to the R203K/G204R Variant in Nucleocapsid: Homologous Recombination has Potential to Change SARS-CoV-2 at Both Protein and RNA Level.Pathogens & immunity · 2021Article
- Review
- Adaptive Immune Response against Hepatitis C Virus.International journal of molecular sciences · 2020Review
- MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans.Science translational medicine · 2020Article
- Exploring the interactions between the human and viral genomes.Human genetics · 2020Review
- Review
- Differential escape of HCV from CD8Journal of viral hepatitis · 2019Article
- Review
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
BACKGROUND AND
aimsCD8 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.
methodsA 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.
resultsA 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.
conclusionsIt 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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