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

Nitschke, Katja; Barriga, Alejandro; Schmidt, Julia; Timm, Jörg; Viazov, Sergei; Kuntzen, Thomas; Kim, Arthur Y.; Lauer, Georg M.; Allen, Todd M.; Gaudieri, Silvana; Rauch, Andri; Lange, Christian M.; Sarrazin, Christoph; Eiermann, Thomas; Sidney, John; Sette, Alessandro; Thimme, Robert; López, Daniel; Neumann-Haefelin, Christoph (2014). HLA-B⁎27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T cell epitope. Journal of hepatology, 60(1), pp. 22-29. Elsevier 10.1016/j.jhep.2013.08.009

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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 (NS5B2820) 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 NS5B2820 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 NS5B2820 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.

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