Abstract
Restoring antiviral immunity is a promising immunotherapeutic approach to the treatment of chronic hepatitis B virus (HBV) infection. Dendritic cells play a crucial role in triggering antiviral immunity. In this study, we identified immunodominant epitopes prevalent in CD8+ T cell responses. We characterized the hierarchy of HBV epitopes targeted by CD8+ T cells following autologous monocyte-derived dendritic cell (moDC) expansion in HBV-infected subjects with distinct disease stages: treatment-naïve (TN group, n = 168), treatment with complete virological response (TR group, n = 72), and resolved HBV infection (RS group, n = 28). T cell responses against 32 HBV epitopes were measured upon moDC expansion. Several subdominant epitopes that triggered HBV-specific CD8+ T cell responses were identified. These epitopes’ responses varied in individuals with different disease stages. Moreover, the most immunodominant and immunoprevalent epitope included the envelope residues 256-270 (Env256-270), corresponding to amino acid residues 93-107 in the small HBV surface protein (SHBs) across three patient groups. The frequency of Env256-270-specific interferon-γ-producing T cells was the highest in the RS group and the lowest in the TN group. In addition, individuals with HLA-A*02:03/02:06/02:07 were capable of responding to Env256-270. Env256-270-specific CD8+ T cells tolerated amino acid variations within the epitope detected in HBV genotypes B and C. This suggests that Env256-270 in SHBs is crucial in HBV-specific T cell immunity following autologous moDC expansion. It might be a potential target epitope for dendritic-cell-based immunotherapy for CHB patients with complete viral suppression by long-term NAs treatment.
Highlights
Over 240 million people worldwide are chronically infected with hepatitis B virus (HBV), resulting in about 1 million deaths per year due to liver failure or liver cancer [1]
Cell-surface markers in the monocyte-derived dendritic cell (moDC) population, including major histocompatibility complex (MHC)-I, CD11c, CD80, CD83 and CD86, were analyzed. The frequencies of these markers did not show any significant differences among these four groups (Supplementary Fig. 1). These data indicated that these autologous moDCs have a similar ability to differentiate regardless of disease stages in HBV infection, and moDC differentiation in the different HBV-infected groups was comparable to that in the uninfected HC group
We examined whether mature hepatitis B surface antigen. MT1 (HBsAg)-pulsed moDCs could be used to expand autologous HBV-specific T cells in chronic hepatitis B (CHB) by testing 80 patients (40 from the TN group and 40 from the TR group) (Supplementary Table 2)
Summary
Over 240 million people worldwide are chronically infected with hepatitis B virus (HBV), resulting in about 1 million deaths per year due to liver failure or liver cancer [1]. Interferon (IFN) and nucleot(s)ide analogues (NAs) are currently approved for antiviral treatment of chronic HBV infection. Immunotherapy has demonstrated some clinical effectiveness in tumors that are associated with an inflammatory or immune response, such as liver cancer, melanoma, and renal cell carcinoma [5,6,7]. It has shown effects on chronic viral infection, including chronic hepatitis B (CHB) [8]. HBV replicates non-cytopathically in hepatocytes, and the virus-related diseases are attributed to chronic immune-mediated inflammatory events [9].
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