The impact of ERAP1 polymorphisms on virus-specific CD8+ T cell responses in an HLA*B27+ patient with acute hepatitis C virus infection

Background/aim: In hepatitis C virus (HCV) infection, HLA-B*27 is associated with spontaneous viral clearance of acute infection. However, some HLA-B*27+ patients develop chronic HCV infection due to an inefficient HCV-specific immune response. In order to determine factors influencing this course of infection we comprehensively characterized an HLA*B27+ patient with acute infection, who controlled the virus to low titers close to the limit of detection but did not completely clear the virus for > 12 months.

Methods: We performed a comprehensive analysis of HCV-specific CD8+ T cell responses in this patient, using overlapping peptides, epitope fine trimming and HLA class I restriction experiments. In addition, we performed genetic analysis and functional testing of the endoplasmic reticulum aminopeptidase 1 (ERAP1) genotype and phenotype of the patient.

Results: We identified a total of 6 HCV-specific CD8+ T cell epitopes targeted in this patient. These epitopes were restricted by HLA-A*01, A*26, B*08, and B*27. Strikingly, some of these epitopes overlapped with previously described epitopes. However, most of the epitopes identified in the patient were longer than usually observed CD8+ T cell epitopes, e.g. consisting of 10 – 11 amino acids instead of 9 amino acids. This phenomenon was most obvious for a previously described HLA-B*27 restricted epitope. This epitope was described as a 9-mer previously, but targeted as an 11-mer in the patient.

The endoplasmic reticulum aminopeptidase 1 (ERAP1) trims peptides in order to generate optimal ligands for HLA molecules. Polymorphisms in the ERAP1 gene are strongly associated with ankylosing spondylitis in HLA*B27+ patients and affect length, quality and quantity of peptides that are loaded onto HLA molecules and presented to CD8+ T cells. We thus speculated that ERAP1 polymorphisms might influence the epitope repertoire in our patient. Indeed, sequencing of the ERAP1 allotypes in this patient revealed polymorphisms in the ERAP1 gene which have been shown to affect trimming activity. Functional testing confirmed that the ERAP1 allotype of the patient displayed reduced peptide trimming activity in comparison to the wildtype ERAP1.

Conclusion: Here we show for the first time that ERAP1 allotypes may have a strong impact on the HCV-specific CD8+ T cell response and may thus influence outcome of infection. These results further indicate that similar mechanisms may contribute to the protective role of HLA-B*27 in viral infections such as HCV and HIV infection on the one hand, and to immunopathogenesis of HLA-B*27 associated rheumatologic disorders on the other hand.