Loss of viral fitness and cross-recognition by CD8(+) T cells limit HCV escape from a protective HLA-B27-restricted human immune response - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Journal of Clinical Investigation Année : 2009

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

Résumé

There is an association between expression of the MHC class I molecule HLA-1327 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-posidve 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-1327 in HCV infection can be explained by the requirement to accumulate a cluster of mutations within the immunodominant epitope to escape T cell recognition.

Dates et versions

hal-02657753 , version 1 (30-05-2020)

Identifiants

Citer

Eva Dazert, Christoph Neumann-Haefelin, Stéphane Bressanelli, Karen Fitzmaurice, Julia Kort, et al.. Loss of viral fitness and cross-recognition by CD8(+) T cells limit HCV escape from a protective HLA-B27-restricted human immune response. Journal of Clinical Investigation, 2009, 119 (2), pp.376-386. ⟨10.1172/JCI36587⟩. ⟨hal-02657753⟩
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