Investigation of immune escape-associated mutations of hepatitis B virus in patients harboring hepatitis B virus drug-resistance mutations  

作　　者：Bi-Xia Huang Yan Liu Zhen-Ping Fan Lan-Lan Si Rong-Juan Chen Jun Wang Dan Luo Fu-Sheng Wang Dong-Ping Xu Xin-Guang Liu 

机构地区：[1]Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics/Institute of Biochemistry&Molecular Biology,Guangdong Medical University,Dongguan 523808,Guangdong Province,China [2]Institute of Infectious Diseases,the Fifth Medical Center of Chinese PLA General Hospital,Beijing 100039,China [3]Department of Infectious Diseases,the First Affiliated Hospital of Xi’an Jiaotong University,Xi’an 710061,Shaanxi Province,China

出　　处：《World Journal of Gastroenterology》2020年第35期5314-5327,共14页世界胃肠病学杂志（英文版）

基　　金：the National Natural Science Foundation of China,No.81572010,No.81671399,No.81721002 and No.81971329;the Capital Health Research and Development of Special Fund Program,No.2016-2-5032;and the Beijing Natural Science Foundation No.7172206.

摘　　要：It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen(HBsAg)are associated with nucleoside/nucleotide analog resistance.AIM To evaluate the association between immune escape-associated mutations and nucleoside/nucleotide analog resistance mutations.METHODS In total,19440 patients with chronic hepatitis B virus infection,who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between July 2007 and December 2017,were enrolled.As determined by sequence analysis,6982 patients harbored a virus with resistance mutations and 12458 harbored a virus lacking resistance mutations.Phenotypic analyses were performed to evaluate HBsAg production,replication capacity,and drug-induced viral inhibition of patient-derived drug-resistant mutants with or without the coexistence of sA159V.RESULTS The rate of immune escape-associated mutation was significantly higher in 9 of the 39 analyzed mutation sites in patients with resistance mutations than in patients without resistance mutations.In particular,these mutations were sQ101H/K/R,sS114A/L/T,sT118A/K/M/R/S/V,sP120A/L/Q/S/T,sT/I126A/N/P/S,sM133I/L/T,sC137W/Y,sG145A/R,and sA159G/V.Among these,sA159V was detected in 1.95%(136/6982)of patients with resistance mutations and 1.08%(134/12,458)of patients lacking resistance mutations(P<0.05).The coexistence of sA159V with lamivudine(LAM)and entecavir(ETV)-resistance mutations in the same viral genome was identified during follow-up in some patients with drug resistance.HBsAg production was significantly lower and the replication capacity was significantly higher,without a significant difference in LAM/ETV susceptibility,in sA159V-containing LAM/ETV-resistant mutants than in their sA159V-lacking counterparts.CONCLUSION In summary,we observed a close link between the increase in certain immune escape-associated mutations and the development of resistance mutations.sA159V might increase the fitness of LAM/ETV-resistant mutants under env

关 键 词：Hepatitis B virus Immune escape-associated mutation Drug-resistance mutation Nucleoside/nucleotide analogs Hepatitis B surface antigen Major hydrophilic region 

分 类 号：R512.62[医药卫生—内科学]