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- Title
The Role of ALPK1 in Inhibiting Hepatitis B Virus Replication Facilitates the Identification of ALPK1 P660L Variant for Predicting Response to Pegylated Interferon α Therapy.
- Authors
Lou, Shuang; Wang, Jialin; Chen, Jiaxuan; Xie, Haisheng; Chen, Haitao; Zhou, Bin; Zhang, Bo; Hou, Jinlin; Jiang, De-Ke
- Abstract
Background Alpha kinase 1 (ALPK1) agonist has recently been reported to demonstrate anti–hepatitis B virus (HBV) efficacy via activating NF-κB signaling, which is crucial for maximizing interferon (IFN) responses. Here, we investigated the impact of ALPK1 on HBV replication and explored ALPK1 variants for predicting the response to pegylated IFN-α (PegIFN-α) treatment. Methods The potential anti-HBV effect of ALPK1 was evaluated in HBV-integrated and HBV-infected hepatoma cells. The potentially functional genetic variants of ALPK1 were screened out, and their correlations with PegIFN-α treatment response were assessed in 945 hepatitis B e antigen (HBeAg)–positive patients with chronic hepatitis B (CHB). Results We revealed that ALPK1 inhibited HBV replication in hepatocytes via activating the JAK-STAT pathway. ALPK1 overexpression improved the anti-HBV effect of IFN-α in cell models. A missense variant, rs35389530 (P660L), of ALPK1 was strongly associated with combined response (CR; namely, HBeAg seroconversion and HBV DNA level <3.3log10 IU/mL) to PegIFN-α treatment in patients with CHB (P = 2.12 × 10−6). Moreover, a polygenic score integrating ALPK1 _rs35389530 and 2 additional genetic variants was further significantly associated with CR (P trend = 9.28 × 10−7), hepatitis B surface antigen (HBsAg) level (P trend =.0002), and HBsAg loss (P trend =.025). Conclusions The anti-HBV effects of ALPK1 through activating JAK-STAT pathway provides a new perspective for CHB therapy. ALPK1 _rs35389530 and polygenic score are potential biomarkers to predict PegIFN-α treatment response and may be used for optimizing CHB treatment.
- Subjects
HEPATITIS B virus; HEPATITIS associated antigen; VIRAL replication; CHRONIC hepatitis B; RIBAVIRIN; JAK-STAT pathway; HEPATITIS B vaccines
- Publication
Journal of Infectious Diseases, 2023, Vol 228, Issue 6, p694
- ISSN
0022-1899
- Publication type
Article
- DOI
10.1093/infdis/jiad065