SLC22A1 Resists Hepatitis B Virus by Activating the JAK/STAT Pathway and Predicts the Effect of Pegylated Interferon α–Based Therapy on Chronic Hepatitis B

BACKGROUND: Functional cure is the ideal treatment endpoint of chronic hepatitis B (CHB). Currently, only a few patients achieve this with treatment. Host differences must be influential. Solute carrier family 22 member 1 (SLC22A1), encoding organic cation transporter 1, is expressed in the liver and mediates substance transport of hepatocytes. The association between SLC22A1 and CHB has not been determined. Our objective was to elucidate this association. METHODS: RNA sequencing was performed to explore the changes caused by hepatitis B virus (HBV) and SLC22A1. Plasma from 200 patients with CHB (120 uncured, 80 cured) completing the pegylated interferon alpha (pegIFNα)-based treatment was collected at baseline and at 12 and 24 weeks of treatment. SLC22A1 of plasma and liver biopsies in healthy controls and patients with CHB were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. RESULTS: SLC22A1 was down-regulated by HBV, as indicated by comparing SLC22A1 of hepG2 cells with and without HBV and of both liver and plasma in CHB and healthy volunteers. Plasma SLC22A1 rose dynamically in the cured group but not in the uncured group. Plasma SLC22A1 at 24 weeks was predictive of functional cure (area under the receiver operating characteristic curve [AUC], 0.887) and better when combined with hepatitis B surface antigen (HBsAg) at 24 weeks (AUC, 0.925). In vitro experiments regarding overexpression of SLC22A1 in hepG2.2.15 demonstrated that HBsAg and hepatitis B e antigen were inhibited by SLC22A1 through JAK/STAT pathway activation, consistent with transcriptome sequencing results. CONCLUSIONS: HBV inhibits SLC22A1 expression and SLC22A1 suppresses HBV by activating the JAK/STAT pathway. SLC22A1 is a predictor of the functional cure of CHB with pegIFNα-based treatment.