Khakpoor, A; Ni, Y; Chen, A; Ho, ZZ; Oei, V; Yang, N; Giri, R; ... Bertoletti, A; + view all Khakpoor, A; Ni, Y; Chen, A; Ho, ZZ; Oei, V; Yang, N; Giri, R; Chow, JX; Tan, AT; Kennedy, PT; Maini, M; Urban, S; Bertoletti, A; - view fewer (2018) Spatio-temporal differences in presentation of CD8 T cell epitopes during HBV infection. Journal of Virology 10.1128/JVI.01457-18. (In press).

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Abstract

Distinct populations of hepatocytes infected with HBV or only harboring HBV-DNA integrations coexist within an HBV chronically infected liver. These hepatocytes express HBV antigens at different levels and with different intracellular localizations but it is not known whether this heterogeneity of viral antigen expression could result in an uneven hepatic presentation of distinct HBV epitopes/HLA class-I complexes triggering different level of activation of HBV-specific CD8+ T cells.Using antibodies specific to two distinct HLA-A*02:01/HBV epitope complexes of HBV nucleocapsid and envelope proteins, we mapped their topological distribution in liver biopsies of two anti-HBe+ chronic HBV (CHB) patients. We demonstrated that the core and envelope CD8+T cell epitopes were not uniformly distributed in the liver parenchyma but preferentially located in distinct and sometimes mutually exclusive hepatic zones. The efficiency of HBV epitope presentation was then tested in vitro utilizing HLA-A*02:01/HBV epitope-specific antibodies and the corresponding CD8+ T cells, in primary human hepatocyte and hepatoma cell lines either infected with HBV or harboring HBV-DNA integration. We confirmed the existence of a marked variability in the efficiency of HLA-class I/HBV epitope presentation among the different targets that was influenced by presence of IFN-γ and availability of newly-translated viral antigens. In conclusion, HBV antigen presentation can be heterogeneous within an HBV-infected liver. As a consequence, CD8+ T cells of different HBV specificities might have different antiviral efficacy.Importance The inability of patients with chronic HBV infection to clear HBV is associated with defective HBV-specific CD8+ T cells. Hence, the majority of immunotherapy developments focus on HBV specific T cell function restoration. However, knowledge of whether distinct HBV-specific T cells can equally target all the HBV-infected hepatocytes of a chronically infected liver are lacking. In this work, analysis of CHB patient liver parenchyma and in vitro HBV infection models shows a non-uniform distribution of HBV CD8+ T cells epitopes that is influenced by presence of IFN-γ and availability of newly-translated viral antigens. These results suggest that CD8+ T cells recognizing different HBV epitopes can be necessary for efficient immune therapeutic control of chronic HBV infection.

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