HLA-B*27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T cell epitope

Background & Aims HLA-B ∗ 27 is associated with spontaneous HCV genotype 1 clearance. HLA-B ∗ 27-restricted CD8+ T cells target three NS5B epitopes. Two of these epitopes are dominantly targeted in the majority of HLA-B ∗ 27+ patients. In chronic infection, viral escape occurs consistently in these two epitopes. The third epitope (NS5B 2820 ) was dominantly targeted in an acutely infected patient. This was in contrast, however, to the lack of recognition and viral escape in the large majority of HLA-B ∗ 27+ patients. Here, we set out to determine the host factors contributing to selective targeting of this epitope. Methods Four-digit HLA class I typing and viral sequence analyses were performed in 78 HLA-B ∗ 27+ patients with chronic HCV genotype 1 infection. CD8+ T cell analyses were performed in a subset of patients. In addition, HLA/peptide affinity was compared for HLA-B ∗ 27:02 and 05. Results The NS5B 2820 epitope is only restricted by the HLA-B ∗ 27 subtype HLA-B ∗ 27:02 (that is frequent in Mediterranean populations), but not by the prototype HLA-B ∗ 27 subtype B ∗ 27:05. Indeed, the epitope is very dominant in HLA-B ∗ 27:02+ patients and is associated with viral escape mutations at the anchor position for HLA-binding in 12 out of 13 HLA-B ∗ 27:02+ chronically infected patients. Conclusions The NS5B 2820 epitope is immunodominant in the context of HLA-B ∗ 27:02, but is not restricted by other HLA-B ∗ 27 subtypes. This finding suggests an important role of HLA subtypes in the restriction of HCV-specific CD8+ responses. With minor HLA subtypes covering up to 39% of specific populations, these findings may have important implications for the selection of epitopes for global vaccines.