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DOI: 10.1055/s-0034-1397260
Viral sequence analysis of the hepatitis B virus core protein reveals CD8 T cell epitopes under reproducible selection pressure
Background: Chronic infections with the hepatitis B virus (HBV) are worldwide an enormous public health problem. Effective suppression of viral replication can be achieved with inhibitors of the viral polymerase, however, in most cases lifelong treatment is required to avoid recurrence of viremia. Activation of HBV-specific CD8 T cells by therapeutic vaccination may promote sustained control of viral replication by clearance of cccDNA from infected hepatocytes. Importantly, little is known about the exact targets of the CD8 T cell response and the extent of selection pressure on the virus. Here, it was hypothesized that CD8 T cell responses associated with strong selection pressure on the virus can be identified by viral sequence analysis.
Methods: The HBV core gene was amplified and sequenced from 148 patients with chronic HBV infection and the HLA class I genotype (A and B locus) was determined. Residues under selection pressure in the presence of particular HLA class I alleles were identified by a statistical approach utilizing a novel analysis package 'SeqFeatR'. Candidate CD8 T cell epitopes were confirmed by analysis of PBMCs from patients with chronic and acute infection.
Results: With a false discovery rate set to 0.2 a total of 9 residues under selection pressure in the presence of 10 different HLA class I alleles were identified. Additional immunological experiments confirmed that 7 of the residues were located inside previously unidentified epitopes targeted in patients with chronic HBV infection carrying the relevant HLA class I allele. Consistent with viral escape some of the selected substitutions impaired recognition by HBV-specific CD8 T cells.
Conclusion: Viral sequence analysis allows identification of HLA class I-restricted epitopes under reproducible selection pressure in HBV core. The possibility of viral adaptation to CD8 T cell immune pressure needs attention in the context of therapeutic vaccination.
Corresponding author: Kefalakes, Helenie
E-Mail: helenie.kefalakes@uk-essen.de