Precore mutation enhances viral replication to facilitate persistent infection especially in HBeAg-negative patients

Guixin Li; Danli Yang; Xin Liu; Ting Zhang; Hui Liu; Jun Zou; Zimeng Xu; Xiangmei Chen; Lizhong Dai; Hongsong Chen; Fengmin Lu

doi:10.1016/j.virs.2024.03.003

April 2024

. doi: 10.1016/j.virs.2024.03.003

Citation: Guixin Li, Danli Yang, Xin Liu, Ting Zhang, Hui Liu, Jun Zou, Zimeng Xu, Xiangmei Chen, Lizhong Dai, Hongsong Chen, Fengmin Lu. Precore mutation enhances viral replication to facilitate persistent infection especially in HBeAg-negative patients .VIROLOGICA SINICA, 2024, 39(2) : 319-330. http://dx.doi.org/10.1016/j.virs.2024.03.003

在HBeAg阴性患者中HBV前核心区突变通过增强病毒复制利于慢性感染维持

李桂馨 ^a ,
杨丹丽 ^b ,
刘新 ^b ,
张婷 ^b ,
刘慧 ^c ,
邹军 ^d ,
许梓萌 ^e ,
陈香梅 ^b ,
戴立忠f ^f,, ,
陈红松 ^a,, ,
鲁凤民 ^a,b,,

a. 北京大学人民医院, 北京大学肝病研究所, 丙型肝炎和肝病免疫治疗北京市重点实验室, 非酒精性脂肪性肝病诊断北京市国际科技合作基地, 北京, 100044, 中国;
b. 北京大学基础医学院, 病原生物学系暨感染病研究中心, 北京, 100191, 中国;
c. Baruch S. Blumberg研究所, 宾夕法尼亚州, 18901, 美国d;
. 深圳市三源生生物科技有限公司, 深圳, 518000, 中国;
e. 郑州大学精准医学中心, 医学科学院, 郑州大学, 郑州, 450001, 中国;
f. 北大-圣湘生物分子医学联合实验室, 圣湘生物科技股份有限公司, 长沙, 410205, 中国

通讯作者： 戴立忠f, lizhongd@sansure.com.cn; 陈红松, chenhongsong@bjmu.edu.cn; 鲁凤民, lu.fengmin@hsc.pku.edu.cn
收稿日期： 2023-09-07
录用日期： 2024-03-11

摘要

自然发生的HBV前核心区（PC，G1896A）和/或基础核心启动子区（BCP，A1762T/G1764A）突变在慢性HBV感染者特别是HBeAg阴性患者中普遍存在。然而，PC/BCP突变病毒的复制能力仍不明确。本文荟萃分析显示，仅在HBeAg阴性状态下，携带PC突变的患者血清HBV DNA水平高于未携带突变的患者。单独PC突变或联合BCP突变在细胞模型和水压动力注射小鼠模型中均促进了HBV复制。在人肝嵌合小鼠感染模型中，PC联合BCP突变促进病毒复制及肝细胞内核心蛋白的表达。机制上，携带PC突变的preC RNA可表达核心蛋白和P蛋白，这种pgRNA样功能有利于HBeAg阴性状态下cccDNA池的维持。此外，PC联合BCP突变病毒感染在人肝嵌合小鼠模型中可能通过激活内质网应激和TNF信号通路导致更为广泛和严重的人肝细胞损伤。本研究表明，HBeAg阴性患者可能需要定期监测HBV突变并尽早接受抗病毒治疗以延缓疾病进展。
- 乙型肝炎病毒
- , 前核心区突变
- , 基础核心启动子区突变
- , 内质网应激

Precore mutation enhances viral replication to facilitate persistent infection especially in HBeAg-negative patients

Guixin Li ^a ,
Danli Yang ^b ,
Xin Liu ^b ,
Ting Zhang ^b ,
Hui Liu ^c ,
Jun Zou ^d ,
Zimeng Xu ^e ,
Xiangmei Chen ^b ,
Lizhong Dai ^f,, ,
Hongsong Chen ^a,, ,
Fengmin Lu ^a,b,,

a. Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China;
b. Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China;
c. Baruch S. Blumberg Institute, Doylestown, PA, 18901, USA;
d. Shenzhen Sanyuansheng Biotechnology Co., Ltd, Shenzhen, 518000, China;
e. Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China;
f. Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Sansure Biotech Co., Ltd, Changsha, 410205, China

Corresponding author: Lizhong Dai, lizhongd@sansure.com.cn Hongsong Chen, chenhongsong@bjmu.edu.cn Fengmin Lu, lu.fengmin@hsc.pku.edu.cn
Received Date: 07 September 2023
Accepted Date: 11 March 2024

Abstract

Naturally occurred precore (PC, G1896A) and/or basal core promoter (BCP, A1762T/G1764A) mutations are prevalent in chronic HBV-infected patients, especially those under HBeAg-negative status. However, the replicative capacity of HBV with PC/BCP mutations remains ambiguous. Herein, meta-analysis showed that, only under HBeAg-negative status, the serum HBV DNA load in patients with PC mutation was 7.41-fold higher than those without the mutation. Both PC mutation alone and BCP + PC mutations promoted HBV replication in cell and hydrodynamic injection mouse models. In human hepatocyte chimeric mouse model, BCP + PC mutations led to elevated replicative capacity and intrahepatic core protein accumulation. Mechanistically, preC RNA harboring PC mutation could serve as mRNA to express core and P proteins, and such pgRNA-like function favored the maintenance of cccDNA pool under HBeAg-negative status. Additionally, BCP + PC mutations induced more extensive and severe human hepatocyte damage as well as activated endoplasmic reticulum stress and TNF signaling pathway in livers of chimeric mice. This study indicates that HBeAg-negative patients should be monitored on HBV mutations regularly and are expected to receive early antiviral treatment to prevent disease progression.
- Hepatitis B virus
- , Precore mutation
- , Basal core promoter mutations
- , Endoplasmic reticulum stress

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