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

J Clin Invest. 2009 Feb;119(2):376-86. doi: 10.1172/JCI36587. Epub 2009 Jan 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Epitopes, T-Lymphocyte
  • HLA-B27 Antigen / chemistry
  • HLA-B27 Antigen / physiology*
  • Hepatitis C / immunology*
  • Humans
  • Immunodominant Epitopes
  • Mutation
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / genetics
  • Virus Replication

Substances

  • Epitopes, T-Lymphocyte
  • HLA-B27 Antigen
  • Immunodominant Epitopes
  • NS-5 protein, hepatitis C virus
  • Viral Nonstructural Proteins