Higher BST2 Expression Promotes the Anti‐HBV Effect of IFN‐α and BST2 Genetic Variant Predicts PegIFNα Treatment Response of HBeAg‐Positive Chronic Hepatitis B Patients

Abstract

We previously reported that an interferon (IFN)‐inducible protein, BST2, was regulated by the JAK–STAT pathway activated by CD40, and subsequently suppressing hepatitis B virus (HBV) repliaction and transcription. The current research attempted to assess the impact of BST2 on the IFN‐treated anti‐HBV effect, and explore BST2 variants for predicting pegylated IFN alpha (PegIFNα) therapy response of patients with hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B (CHB). Using an HBV‐transfected cell model, the function of BST2 on HBV DNA replication and transcription driven by IFN was studied. The potentially functional BST2 variants were selected through a strategy of gene‐wide screening. The associations of BST2 variants and polygenic score (PGS) model, which was used to quantify the combined influence of several genetic variants, with treatment response were examined in 2 separate PegIFNα‐treated cohorts of 238 and 707 patients with CHB, respectively. We found that overexpression of BST2 improved the anti‐HBV activity triggered by IFN‐α. Among PegIFNα‐treated patients with CHB, BST2_rs9576 was screened out to be significantly correlated with combined response (CR; i.e., HBeAg seroconversion along with HBV DNA level <3.3log10IU/mL, P = 7.12 × 10−5). Additionally, there was a strong correlation between the PGS incorporating BST2_rs9576 and other 5 genetic variations (previously described predictors of therapy response to PegIFNα) and CR (P = 1.81 × 10−13), hepatitis B surface antigen (HBsAg) level (P = 0.004), as well as HBsAg decline (P = 0.017). In conclusion, higher BST2 expression responded better to IFN‐α treatment. BST2_rs9576 is an effective indicator to forecast therapy response of PegIFNα‐treated patients with CHB. The PGS possesses the potential to boost the ability of PegIFNα therapy response.