Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response

• Published in: The Journal of clinical investigation 2009-02, Vol.119 (2), p.376-386
• Main Authors: Dazert, Eva, Neumann-Haefelin, Christoph, Bressanelli, Stéphane, Fitzmaurice, Karen, Kort, Julia, Timm, Jörg, McKiernan, Susan, Kelleher, Dermot, Gruener, Norbert, Tavis, John E, Rosen, Hugo R, Shaw, Jaqueline, Bowness, Paul, Blum, Hubert E, Klenerman, Paul, Bartenschlager, Ralf, Thimme, Robert
• Format: Article
• Language: English
• Subjects: Binding Sites; Biomedical research; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Epitopes, T-Lymphocyte; Hepatitis C - immunology; HIV; HLA-B27 Antigen - chemistry; HLA-B27 Antigen - physiology; Human immunodeficiency virus; Humans; Immunodominant Epitopes; Infections; Life Sciences; Lymphocytes; Mutation; Patients; Peptides; RNA polymerase; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Virus Replication
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI36587

There is an association between expression of the MHC class I molecule HLA-B27 and protection following human infection with either HIV or HCV. In both cases, protection has been linked to HLA-B27 presentation of a single immunodominant viral peptide epitope to CD8+ T cells. If HIV mutates the HLA-B27-binding anchor of this epitope to escape the protective immune response, the result is a less-fit virus that requires additional compensatory clustered mutations. Here, we sought to determine whether the immunodominant HLA-B27-restricted HCV epitope was similarly constrained by analyzing the replication competence and immunogenicity of different escape mutants. Interestingly, in most HLA-B27-positive patients chronically infected with HCV, the escape mutations spared the HLA-B27-binding anchor. Instead, the escape mutations were clustered at other sites within the epitope and had only a modest impact on replication competence. Further analysis revealed that the cluster of mutations is required for efficient escape because a combination of mutations is needed to impair T cell recognition of the epitope. Artificially introduced mutations at the HLA-B27-binding anchors were found to be either completely cross-reactive or to lead to substantial loss of fitness. These results suggest that protection by HLA-B27 in HCV infection can be explained by the requirement to accumulate a cluster of mutations within the immunodominant epitope to escape T cell recognition.