Mutational escape from CD8+ T cell immunity: HCV evolution, from chimpanzees to man

Abstract

The mechanisms by which the hepatitis C virus (HCV) establishes persistence are not yet fully understood. Previous chimpanzee and now human studies suggest that mutations within MHC class I-restricted HCV epitopes might contribute to viral escape from cytotoxic T lymphocyte (CTL) responses. However, there are several outstanding questions regarding the role of escape mutations in viral persistence and their fate in the absence of immune selection pressure.

Figure 1.

Mechanisms of CTL escape after mutation in cognate epitopes. (A) Wild-type peptide is correctly processed, binds to MHC, and the resulting complex is recognized by the relevant TCR, triggering a CTL response. (B) Mutations in anchoring residues may lead to dissociation of the MHC–peptide complex. (C) Mutations in the epitope or in flanking regions can alter proteosomal processing, leading to destruction of the epitope. (D) Mutated epitopes may bind MHC; however, TCR recognition may be reduced or possibly altered, leading to antagonism against responses to the wild-type peptide.

Figure 2.

Evolution of HCV epitopes after infection. (A) Where a restricting allele is present, immune factors such as a sustained CD4⁺ T cell response and diverse clonal CTL TCR repertoire may constrain the development of escape mutations; this may be association with viral clearance. (B) Where the CD4⁺ T cell response fails and/or the clonal CTL TCR repertoire is narrow, escape mutations may emerge. Development of an escape mutation may require additional compensatory mutations. (C) If CTL responses are weak or absent, escape mutations may not develop. (D) In the absence of the restricting allele, where there is high fitness cost associated with the presence of an escape mutation, reversion to wild-type sequence is likely to occur because of minimal immune selection pressure. (E) When there is low associated fitness cost or well developed compensatory mutations in the absence of immune selection pressure, the mutated sequence may persist, or perhaps might mutate to an equally fit alternative.