Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27–restricted human immune response
Eva Dazert, … , Ralf Bartenschlager, Robert Thimme
Eva Dazert, … , Ralf Bartenschlager, Robert Thimme
Published January 12, 2009
Citation Information: J Clin Invest. 2009;119(2):376-386. https://doi.org/10.1172/JCI36587.
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Research Article Virology

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

Abstract

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.

Authors

Eva Dazert, Christoph Neumann-Haefelin, Stéphane Bressanelli, Karen Fitzmaurice, Julia Kort, Jörg Timm, Susan McKiernan, Dermot Kelleher, Norbert Gruener, John E. Tavis, Hugo R. Rosen, Jaqueline Shaw, Paul Bowness, Hubert E. Blum, Paul Klenerman, Ralf Bartenschlager, Robert Thimme

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Figure 5

Structural analysis of the epitope.

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Structural analysis of the epitope. (A) NS5B displayed as ribbons and co...
(A) NS5B displayed as ribbons and colored according to individual domains (red: fingers; yellow: palm; blue: thumb). The epitope is shown in blue-green. (B) Close-up of the epitope region. Residues mutated in this study are shown in stick representation and colored according to atom type (N: blue; O: red; S: orange; C: blue-green). Four of these residues are labeled. Also labeled are helices Q (which harbors the epitope) and A (from the “fingertips”), as well as non-nucleoside inhibitor (NNI) site B. Note that helix Q is both central to the thumb’s folding domain and involved in the NNI pockets’ buildup. (C) Interactions of R2842 with neighboring residues. (D and E) Models of the same region after replacement of R2842 with lysine (variant B1) or glutamine (variant B2). (F) Interactions of I2844 with neighboring residues. (G) Model of the variant S2 containing the I2844V substitution. (H) Interactions of T2847 with neighboring residues. In C, F, and H, the neighboring residues are shown as sticks, with carbons in white; hydrogen bonds are represented as dotted yellow lines. (I and J) Models of the variants containing substitution T2847S (S4) and T2847P (S5), respectively.