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 1

Escape mutations within the NS5B2841–2849 epitope are clustered and spare HLA-B27–binding anchors.

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Escape mutations within the NS5B2841–2849 epitope are clustered and spar...
(A) Amino acid sequence of NS5B2841–2849. Upward-pointing open arrows indicate residues that are predicted to interact with the TCR; downward-pointing filled arrows indicate HLA-B27–binding anchors (16). Autologous viral sequences found in 15 HLA-B27+ patients with chronic genotype 1 HCV infection are shown below; points indicate homologous residues (8). (B) Numbers of amino acid substitutions per escape variant are compared in HLA-B27+ and HLA-B27– subjects. Sequences for HLA-B27– subjects were taken from the literature: for acute HCV infection, longitudinal sequences or sequences from a known donor and the patient were compared (22–27), while for chronic HCV infection, patient sequences were compared with genotype/subtype-matched consensus sequences (24, 28–33). Sequences in HLA-B27+ patients with chronic HCV infection were included from this study (Figure 1A) and from a previous, independent report (32). P values were calculated using Mann-Whitney U test.