HLA-B*27-restricted CD8+ T cell response against hepatitis B virus: viral escape as central mechanism of T cell failure

Question Approx. 250 million people worldwide are chronically infected with the hepatitis B virus (cHBV) and are thus at high risk of progressive liver disease. Virus-specific CD8+ T cells play a major role in the control and clearance of HBV infections; however, the mechanisms of CD8+ T-cell failure in cHBV infection have only been partially elucidated, especially the role of viral escape. Since viral escape has been demonstrated in HCV and HIV infection in the context of HLA-B*27, we speculated that HLA-B*27 may also have a dominant role in driving viral escape in HBV infection.

Methods Through footprint analysis of 17 HLA-B*27 positive and 97 HLA-B*27 negative patients with cHBV genotype D infection and in silico epitope prediction, HLA-B*27-restricted HBV-specific CD8+ T-cell epitopes were identified and confirmed by in vitro antigen-specific expansion. The presence of CD8+ T-cell responses targeting the new epitopes was also tested in acute-resolving patients. Epitopes found through footprint analysis were analyzed for viral escape in cHBV infected patients. Phenotypical analysis was performed by MHC-class I tetramer-based enrichment.

Results 12 (5 by in silico prediction; 7 by footprint analysis) HLA-B*27-restricted HBV-specific CD8+ T-cell epitopes were identified. Epitopes identified by in silico prediction were dominantly targeted in both acute-resolving and cHBV infection, whereas epitopes identified by footprint analysis were preferentially targeted in cHBV. The ex vivo frequencies of HLA-B*27-restricted HBV-specific CD8+ T cells targeting conserved epitopes and variant epitopes were similar. After enrichments, the non-naïve T-cell population showed a PD1+CD127+ memory-like phenotype. The transcription factors TOX, TCF1 and Tbet were similarly expressed in HLA-B*27-restricted HBV-specific CD8+ T cells targeting conserved epitopes and variant epitopes. Interestingly, the expression pattern of Eomes and the inhibitory receptor KLRG1 was significantly higher in HBV-specific CD8+ T cells targeting conserved epitopes compared to CD8+ T cells targeting variant epitopes, indicating a more exhausted phenotype of CD8+ T cells targeting wildtype epitopes.

Conclusions cHBV and acute-resolving HBV infected patients exhibited a different CD8+ T-cell repertoire, which may have further implication on HBV chronicity. Further, viral escape may play an important role in HBV infection and may specifically affect CD8+ T-cell epitopes that are targeted during chronic infection only.

Publikationsverlauf

Artikel online veröffentlicht:
04. Januar 2021