Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response.
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-B...
| Päätekijät: | , , , , , , , , , , , , , , , , |
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| Aineistotyyppi: | Journal article |
| Kieli: | English |
| Julkaistu: |
2009
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| _version_ | 1826268619945803776 |
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| author | Dazert, E Neumann-Haefelin, C Bressanelli, S Fitzmaurice, K Kort, J Timm, J McKiernan, S Kelleher, D Gruener, N Tavis, J Rosen, H Shaw, J Bowness, P Blum, H Klenerman, P Bartenschlager, R Thimme, R |
| author_facet | Dazert, E Neumann-Haefelin, C Bressanelli, S Fitzmaurice, K Kort, J Timm, J McKiernan, S Kelleher, D Gruener, N Tavis, J Rosen, H Shaw, J Bowness, P Blum, H Klenerman, P Bartenschlager, R Thimme, R |
| author_sort | Dazert, E |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:12:29Z |
| format | Journal article |
| id | oxford-uuid:3ea6ebc4-ffb7-41a6-98ac-210489d9e6d0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:12:29Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:3ea6ebc4-ffb7-41a6-98ac-210489d9e6d02022-03-26T14:26:51ZLoss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3ea6ebc4-ffb7-41a6-98ac-210489d9e6d0EnglishSymplectic Elements at Oxford2009Dazert, ENeumann-Haefelin, CBressanelli, SFitzmaurice, KKort, JTimm, JMcKiernan, SKelleher, DGruener, NTavis, JRosen, HShaw, JBowness, PBlum, HKlenerman, PBartenschlager, RThimme, RThere 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. |
| spellingShingle | Dazert, E Neumann-Haefelin, C Bressanelli, S Fitzmaurice, K Kort, J Timm, J McKiernan, S Kelleher, D Gruener, N Tavis, J Rosen, H Shaw, J Bowness, P Blum, H Klenerman, P Bartenschlager, R Thimme, R Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. |
| title | Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. |
| title_full | Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. |
| title_fullStr | Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. |
| title_full_unstemmed | Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. |
| title_short | Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. |
| title_sort | loss of viral fitness and cross recognition by cd8 t cells limit hcv escape from a protective hla b27 restricted human immune response |
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