State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China.
J Infect Dis. 2023 Sep 15;228(6):694-703. doi: 10.1093/infdis/jiad065.
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.
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).
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 (Ptrend = 9.28 × 10-7), hepatitis B surface antigen (HBsAg) level (Ptrend = .0002), and HBsAg loss (Ptrend = .025).
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.
最近有报道称，α激酶 1（ALPK1）激动剂通过激活 NF-κB 信号通路发挥抗乙型肝炎病毒（HBV）作用，该信号通路对于最大限度地提高干扰素（IFN）反应至关重要。在这里，我们研究了 ALPK1 对 HBV 复制的影响，并探索了 ALPK1 变体以预测对聚乙二醇化干扰素-α（PegIFN-α）治疗的反应。
在 HBV 整合和 HBV 感染的肝癌细胞中评估了 ALPK1 的潜在抗 HBV 作用。筛选出 ALPK1 的潜在功能遗传变异体，并在 945 例乙型肝炎 e 抗原（HBeAg）阳性的慢性乙型肝炎（CHB）患者中评估其与 PegIFN-α治疗反应的相关性。
我们揭示了 ALPK1 通过激活 JAK-STAT 通路抑制肝细胞中的 HBV 复制。ALPK1 的过表达改善了 IFN-α在细胞模型中的抗 HBV 作用。ALPK1 的错义变体 rs35389530（P660L）与 CHB 患者 PegIFN-α治疗的联合应答（即 HBeAg 血清学转换和 HBV DNA 水平<3.3log10 IU/mL）强烈相关（P=2.12×10-6）。此外，整合 ALPK1_rs35389530 和另外 2 个遗传变异体的多基因评分与 CR（Ptrend=9.28×10-7）、乙型肝炎表面抗原（HBsAg）水平（Ptrend=0.0002）和 HBsAg 丢失（Ptrend=0.025）进一步显著相关。
ALPK1 通过激活 JAK-STAT 通路发挥抗 HBV 作用为 CHB 治疗提供了新视角。ALPK1_rs35389530 和多基因评分是预测 PegIFN-α治疗反应的潜在生物标志物，可用于优化 CHB 治疗。
