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

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

机构地区：[1]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 [2]Department of Microbiology and Infectious Disease Center,School of Basic Medical Sciences,Peking University,Beijing,100191,China [3]Baruch S.Blumberg Institute,Doylestown,PA,18901,USA [4]Shenzhen Sanyuansheng Biotechnology Co.,Ltd,Shenzhen,518000,China [5]Precision Medicine Center of Zhengzhou University,Academy of Medical Sciences,Zhengzhou University,Zhengzhou,450001,China [6]Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine,Sansure Biotech Co.,Ltd,Changsha,410205,China

出　　处：《Virologica Sinica》2024年第2期319-330,共12页中国病毒学（英文版）

基　　金：supported by National Key R&D Program of China(2023YFC2306800);National Natural Science Foundation of China(No.82072280 and No.82272315);Beijing Municipal Natural Science Foundation(No.7212063 and No.7222108).

摘　　要：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 BCPþPC mutations promoted HBV replication in cell and hydrodynamic injection mouse models.In human hepatocyte chimeric mouse model,BCPþPC 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,BCPþPC 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.

关 键 词：Hepatitis B virus Precore mutation Basal core promoter mutations Endoplasmic reticulum stress 

分 类 号：R373.13[医药卫生—病原生物学]