Antiviral Research. 2023 May
Xiu-Qing Pang, Xing Li, Wei-Hang Zhu, Run-Kai Huang, Zhi-shuo Mo, Ze-Xuan Huang, Yuan Zhang, Dong-Ying Xie, Zhi-Liang Gao
Products used in the paper Details Operation
AAV-HBV-002 The adeno-associated virus (AAV)/HBV mouse model was established via tail vein injection of 2.5 × 10^11 copies of AAV8-HBV1.3 viral genome (Shi et al., 2019) (Packgene, AAV-HBV-002). Request Quote

Research Field: HBV treatment

Keywords: HBsAg seroclearance, Erythroid progenitor cells, Lymphocyte-activation gene 3 (LAG3), Transforming growth factor β (TGF-β), Pegylated interferon

AAV Serotype: AAV-HBV

Dose: The adeno-associated virus (AAV)/HBV mouse model was established via tail vein injection of 2.5 × 10^11 copies of AAV8-HBV1.3 viral genome (Shi et al., 2019) (Packgene, AAV-HBV-002).

Routes of Administration: tail vein injection

Abstract

HBsAg seroclearance, the ideal aim of anti-hepatitis B virus (HBV) treatment, cannot be achieved easily. Anemia is another common issue for chronic hepatitis B (CHB) patients, which leads to elevation of erythroid progenitor cells (EPCs) and immune suppression in cancer. This study investigated the role of EPCs in HBsAg seroclearance following pegylated interferon-α (PEG-IFN) treatment. CD45+EPC accumulation in CHB patients and an AAV/HBV mice model was found in the circulation and liver by flow cytometry and immunofluorescence tests. Wright-Giemsa staining showed that these pathological CD45+EPCs presented elevated erythroid cells with relative immature morphologies and atypical cells compared with the control cells. CD45+EPCs were associated with immune tolerance and decreased HBsAg seroclearance during finite PEG-IFN treatment. CD45+EPCs suppressed antigen non-specific T cell activation and HBV-specific CD8+T cells, partially through transforming growth factor β (TGF-β). RNA-seq revealed that CD45+EPCs in patients with CHB presented a distinct gene expression profile compared with CD45−EPCs and CD45+EPCs from cord blood. Notably, CD45+EPCs from patients with CHB expressed high level of Lymphocyte-activation gene 3 (LAG3), an immune checkpoint molecule, and were then defined as LAG3+EPCs. LAG3+EPCs diminished the function of antigen presenting cells through LAG3, which was another mechanism by which LAG3+EPCs’ suppressed HBV-specific CD8+T cells. Anti-LAG3 and anti-TGF-β combination treatment decreased serum HBeAg, HBV DNA levels and HBsAg level, as well as HBsAg-expression in hepatocytes during PEG-IFN treatment in the AAV/HBV mice model. Conclusions: LAG3+EPCs inhibited the efficacy of PEG-IFN treatment on HBsAg seroclearance induced by LAG3 and TGF-β. Anti-LAG3, anti-TGF-β and PEG-IFN combination treatment might facilitate HBV clearance.

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