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

<p>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 <em>BST2</em> 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 <em>BST2</em> 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, <em>BST2</em>_rs9576 was screened out to be significantly correlated with combined response (CR; i.e., HBeAg seroconversion along with HBV DNA level <3.3log₁₀IU/mL, <em>P</em> = 7.12 × 10⁻⁵). Additionally, there was a strong correlation between the PGS incorporating <em>BST2</em>_rs9576 and other 5 genetic variations (previously described predictors of therapy response to PegIFNα) and CR (<em>P</em> = 1.81 × 10⁻¹³), hepatitis B surface antigen (HBsAg) level (<em>P</em> = 0.004), as well as HBsAg decline (<em>P</em> = 0.017). In conclusion, higher BST2 expression responded better to IFN-α treatment. <em>BST2</em>_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.<br></p>