Virus-specific CD8 T cell response seems to play a significant role in the outcome of hepatitis delta virus (HDV)
infection. However, the HDV-specific
T cell epitope repertoire and mechanisms of CD8 T cell failure in HDV
infection have been poorly characterized. We therefore aimed to characterize HDV-specific CD8
T cell epitopes and the impacts of viral mutations on immune escape. In this study, we predicted
peptide epitopes binding the most frequent
human leukocyte antigen (HLA) types and assessed their HLA binding capacities. These
epitopes were characterized in HDV-infected patients by intracellular
gamma interferon (IFN-γ) staining. Sequence analysis of
large hepatitis delta antigen (L-
HDAg) and HLA typing were performed in 104 patients. The impacts of substitutions within
epitopes on the CD8 T cell response were evaluated experimentally and by in silico studies. We identified two
HLA-B*27-restricted CD8
T cell epitopes within L-
HDAg. These novel
epitopes are located in a relatively conserved region of L-
HDAg. However, we detected molecular footprints within the
epitopes in
HLA-B*27-positive patients with chronic HDV
infections. The variant
peptides were not cross-recognized in
HLA-B*27-positive patients with resolved HDV
infections, indicating that the substitutions represent viral escape mutations. Molecular modeling of
HLA-B*27 complexes with the L-
HDAg epitope and its potential viral escape mutations indicated that the structural and electrostatic properties of the bound
peptides differ considerably at the
T cell receptor interface, which provides a possible molecular explanation for the escape mechanism. This viral escape from the
HLA-B*27-restricted CD8 T cell response correlates with a chronic outcome of
hepatitis D infection. T cell failure resulting from immune escape may contribute to the high chronicity rate in HDV
infection.IMPORTANCE Hepatitis delta virus (HDV) causes severe
chronic hepatitis, which affects 20 million people worldwide. Only a small number of patients are able to clear the virus, possibly mediated by a virus-specific T cell response. Here, we performed a systematic screen to define CD8
epitopes and investigated the role of CD8 T cells in the outcome of
hepatitis delta and how they fail to eliminate HDV. Overall the number of
epitopes identified was very low compared to other hepatotropic viruses. We identified, two
HLA-B*27-restricted
epitopes in patients with resolved
infections. In
HLA-B*27-positive patients with chronic HDV
infections, however, we detected escape mutations within these identified
epitopes that could lead to viral evasion of immune responses. These findings support evidence showing that
HLA-B*27 is important for virus-specific CD8 T cell responses, similar to other
viral infections. These results have implications for the clinical prognosis of HDV
infection and for
vaccine development.