切换至 "中华医学电子期刊资源库"

中华实验和临床感染病杂志(电子版) ›› 2018, Vol. 12 ›› Issue (04) : 402 -408. doi: 10.3877/cma.j.issn.1674-1358.2018.04.017

所属专题: 文献

论著

不同基因型HBV对药物反应性和S基因突变位点研究
朱杰华1,(), 黄嘉玲2, 王江林2, 何应中1, 杜文胜1, 黄健1   
  1. 1. 563000 遵义市,遵义医学院附属医院医学检验科
    2. 563099 遵义市,遵义医学院医学检验系医学检验2012级K-1班
  • 收稿日期:2017-10-07 出版日期:2018-08-15
  • 通信作者: 朱杰华
  • 基金资助:
    贵州省联合基金(No.黔科合LH字[2015]7478号)

Drug reactivity and mutations of S gene from different genotypes of hepatitis B virus

Jiehua Zhu1,(), Jialing Huang2, Jianglin Wang2, Yingzhong He1, Wensheng Du1, Jiang Huang1   

  1. 1. Department of Medical Labotory, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
    2. Department of Laboratory Medicine, Zunyi Medical College and Institute of Science and Technology, Zunyi 563099, China
  • Received:2017-10-07 Published:2018-08-15
  • Corresponding author: Jiehua Zhu
  • About author:
    Corresponding author: Zhu Jiehua, Email:
引用本文:

朱杰华, 黄嘉玲, 王江林, 何应中, 杜文胜, 黄健. 不同基因型HBV对药物反应性和S基因突变位点研究[J/OL]. 中华实验和临床感染病杂志(电子版), 2018, 12(04): 402-408.

Jiehua Zhu, Jialing Huang, Jianglin Wang, Yingzhong He, Wensheng Du, Jiang Huang. Drug reactivity and mutations of S gene from different genotypes of hepatitis B virus[J/OL]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2018, 12(04): 402-408.

目的

分析HBV不同基因型对药物反应性及S基因变异情况。

方法

收集遵义医学院附属医院于2016年3月至2017年7月就诊的186例HBV DNA阳性乙型肝炎患者的血清样本,根据是否用药分为治疗组130例和对照组56例,治疗组根据用药不同分为干扰素组、核苷(酸)类似物组、保肝药组和中成药组,分别提取HBV DNA后扩增S基因并测序,结合临床资料分析疗效与基因型相关性。

结果

对照组共51例患者扩增出S基因[91.1%(51/56),其中B基因型30例,C基因型21例],治疗组共有104例患者样本扩增出S基因[80.0%(104/130),其中B基因型62例,C基因型42例],均以B、C基因型为主。两种基因型对核苷(酸)类似物的反应性(肝功能改变、HBVDNA拷贝数)与未治疗组差异有统计学意义(P < 0.01)。B基因型HBV S基因经核苷(酸)类似物作用后,第597位碱基鸟嘌呤G变为腺嘌呤A即183位苯丙氨酸(Phe/F)突变为缬氨酸(Val/V),使翻译终止。保肝药和干扰素引起131位鸟嘌呤G突变为腺嘌呤A,进而甘氨酸(Gly/G)变为谷氨酸(Glu/E),且9和213位氨基酸突变率为100%。C基因型HBV则发生26位胞嘧啶C突变为胸腺嘧啶T,即脯氨酸(P)变为亮氨酸(L)及53位点丝氨酸(Ser/S)突变为亮氨酸L。保肝药物作用主要引起68位点异亮氨酸(Ile/I)突变为苏氨酸(Thr/T)和49位点P变L。干扰素和中成药均可引起225位酪氨酸-异亮氨酸(YI)变为异亮氨酸-组氨酸(IH)和9位氨基酸P变L。

结论

不同HBV基因型对药物反应不同,B、C基因型HBV对药物反应可产生相同突变位点。

Objective

To investigate the different genotypes of HBV on drug reactivity and variation of S gene.

Methods

Total of 186 specimens of hepatitis B patients with HBV DNA positive were collected in Affiliated Hospital of Zunyi Medical University from March of 2016 to July of 2017. According to whether or not using drugs, 186 specimens were divided into experimental group with 130 cases and control group with 56 cases. And the experimental group was divided into interferon group, nucleoside analogue group, hepatoprotective drug group, and Chinese Traditional Medicine group. HBV DNA were extracted and amplified and S gene were sequenced. While the correlation between genotype and clinical treatment were analyzed by clinical data analysis.

Results

S gene were amplified in 91.1% (51/56) samples in untreated group and 80.0% (104/130) samples in experimental group, mainly with B and C genotypes. The reactivity of the two genotypes (the changes of ALT, AST and HBV DNA) were significantly different compared with untreated group (P< 0.01). After reacted with nucleos(t)ide analogues, guanine at the 597th alkaline of S gene in B genotype mutated to adenine, and Phenylalanine (Phe/F) at the 183rd amino acid mutated to valine (Val/V), then translation was terminated. The hepatoprotective drugs and interferon mainly cause the 131st guanine changed to adenine, and Glycine (Gly/G) mutated to glutamic acid (Glu/E), the mutation rate of the 9th and 213rd amino acid were 100%. Among the C genotype, cytosine at the 26th site mutated to thymine, then Proline (Pro/P) mutated to Leucine (Leu/L) and serine (Ser/S) at the 53rd site mutated into Leu. In the hepatoprotective drugs group, Isoleucine mutated to Threonine at the 68th site and P changed into L at the 49th site. Interferon and Chinese Traditional Medicine caused a common mutation with 225 bit Tyrosine-Isoleucine (TI) changing into Isoleucine-Hlstidinein (IH) for both genotype B and C HBV, and the 9th Proline mutated to Leucine.

Conclusions

Different genotypes of HBV showed different reactivity to drugs, genotypes B and C could show the same mutation sites in S gene.

表1 HBV S基因引物序列表
图1 各基因型的同源性
图2 S基因测序结果部分峰图
表2 62例HBV B基因型对不同药物的应答( ±s
表3 42例HBV C基因型对不同药物的应答(±s
表4 药物作用后HBV B基因型S基因碱基及氨基(酸)突变位点[例(%)]
表5 药物作用后HBV C基因型S基因碱基及氨基酸突变位点[例(%)]
表6 药物作用后HBV B与C基因型相同突变位点[例(%)]
[1]
Ganem D,Prince AM. Hepatitis B virus infection natural history and clinical consequences[J]. N Engl J Med,2014,350(10):1118-1129.
[2]
樊蓉,孙剑,侯金林. 慢性乙型肝炎抗病毒治疗现状及展望[J]. 临床肝胆病杂志,2016,32(11):2029-2032.
[3]
Ghasemi F,Rostami S,Ghayour-Mobarhan M, et al. Current progress in the development of therapeutic vaccines for chronic hepatitis B virus infection[J]. Iran J Basic Med Sci,2016,19(7):692-704.
[4]
Chen DS. Hepatitis B vaccination: The key towards elimination and eradication of hepatitis B[J]. J Hepatol,2009,50(4):805-816.
[5]
Mobini M,Mortazavi M,Nadi S, et al. Significant roles played by interleukin-10 in outcome of pregnancy[J]. Iran J Basic Med Sci,2016,19(2):119-124.
[6]
Bertoletti A,Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection[J]. Postgrad Med J,2013,89(1051):294-304.
[7]
Liang TJ,Block TM,Brian J, et al. Present and future therapies of hepatitis B: from discovery to cure[J]. Hepatology,2015,62(6):1893-1908.
[8]
Dienstag JL. Hepatitis B virus infection[J]. N Engl J Med,2008,359(14):1486-1500.
[9]
Lok AS,Zoulim F,Locarnini S, et al. Antiviral drug-resistant HBV: Standardization of nomenclature and assays and recommendations for management[J]. Hepatology,2007,46(1):254-265.
[10]
Gu LJ,Han Y,Li YJ, et al. Emergence of lamivudine-resistant HBV during antiretroviral therapy including lamivudine for patients coinfected with HIV and HBV in China[J]. PLoS One,2015,10(8):e0134539.
[11]
Pau AK,George JM. Antiretroviral therapy: current drugs[J]. Infect Dis Clin North Am,2014,28(3):371-402.
[12]
邱宁,李蕊,温春阳, 等. 慢性乙型肝炎患者在核苷(酸)类药物规范化治疗前耐药突变研究[J]. 中国病毒病杂志,2014,4(1):11-14.
[13]
Chen L,Gan QR,Zhang DQ, et al. Increased intrahepatic quasispecies heterogeneity correlates with offtreatment sustained response to nucleos(t)ide analogues in e antigen-positive chronic hepatitis B petients[J]. Clin Microbiol infec,2016.22(2):201-207.
[14]
Isorce N,Lucifora J,Zoulim F, et al. Immune-modulators to combat hepatitis B virus infection: from IFN-alpha to novel investigational immunotherapeutic strategies[J]. Antiviral Res,2015,122:69-81.
[15]
Gish R,Jia J,Locarnini S, et al. Selection of chronic hepatitis B therapy with high barrier to resistance[J]. Lancet Infect Dis,2012,12(4):341-353.
[16]
Cai WJ,Yin L,Wang SL, et al. Correlation between polymorphisms of the E-selectin gene, hepatitis B virus DNA copies, pre-S1 antigen and clinical outcomes during chronic hepatitis B[J]. Int J Clin Exp Med,2015,8(2):2893-2898.
[17]
Makvandi M. Update on occult hepatitis B virus infection[J]. World J Gastroenterol,2016,22(39):8720-8734.
[18]
Zhang ZH,Wu CC,Chen XW, et al. Genetic variation of hepatitis B virus and its significance for pathogenesis[J]. World J Gastroenterol, 2016,22(1):126-144.
[19]
Rodriguez-Frias F,Buti M,Tabernero D, et al. Quasispecies structure, cornerstone of hepatitis B virus infection: Mass sequencing approach[J]. World J astroenterol,2013,19(41):6995-7023.
[20]
Wang YW,Shan XF,Liang Z, et al. Deep sequencing analysis of HBV genotype shift and correlation with antiviral efficiency during adefovir dipivoxil Therapy[J]. PLoS One,2015,10(6):e0131337.
[21]
杨柳. 乙肝病毒基因型及基因变异特征分析的研究[J]. 中国优生与遗传杂志,2015,23(5):9-19.
[22]
王丽丽,杨兴林,吴君, 等. 贵州地区269例慢性乙型肝炎患者病毒基因型与耐药分析[J]. 实用医学杂志,2016,32(23):3874-3878.
[23]
Sun HY,Sheng WH,Tsai MS, et al. Hepatitis B virus coinfection in human immunodeficiency virus-infected patients: A review[J]. World J Gastroenterol,2014,20(40):14598-14614.
[24]
Zhang ZH,Zhang L,Dai Y, et al. Occult hepatitis B virus infection: influence of S protein variants[J]. Virology,2016,13(10):50-61.
[1] 盛志强, 袁嫣然. ATP1A3基因突变相关疾病1个家系报道及文献复习[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(03): 331-338.
[2] 张雪灵, 陈玮彬, 魏雯硕, 陈明, 诸宏伟. 努南综合征的临床特点与治疗效果分析[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(02): 192-199.
[3] 张禾璇, 杨雪, 王侣金, 李林洁, 刘兴宇. 新生儿葡萄糖-6-磷酸脱氢酶缺乏症筛查及基因突变特征分析[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(02): 200-208.
[4] 张静, 刘畅, 华成舸. 妊娠期患者口腔诊疗进展[J/OL]. 中华口腔医学研究杂志(电子版), 2024, 18(05): 340-344.
[5] 严华悦, 刘子祥, 周少波. 磷酸烯醇式丙酮酸羧激酶-1在恶性肿瘤中的研究进展[J/OL]. 中华普通外科学文献(电子版), 2024, 18(06): 452-456.
[6] 潘冬生, 梁国标. 颅脑创伤治疗的最新进展与未来趋势[J/OL]. 中华神经创伤外科电子杂志, 2024, 10(04): 193-197.
[7] 汤畅通, 王永楠, 王诗筌. 颅脑外伤后阵发性交感神经兴奋患者的药物治疗效果分析[J/OL]. 中华神经创伤外科电子杂志, 2024, 10(04): 233-237.
[8] 吴天宇, 刘子璇, 杨浦鑫, 贾思明, 丁凯, 程晓东, 李泳龙, 陈伟, 吕红芝, 张奇. 腰椎间盘突出症保守治疗进展[J/OL]. 中华老年骨科与康复电子杂志, 2024, 10(06): 379-384.
[9] 李金星, 陈志宏, 孙铭均, 孙岩岩, 党树伟, 李广恩, 彭书奇, 付大伟, 李宏伟, 李国东. 基于多层螺旋CT 的腹腔干解剖变异与新分型研究[J/OL]. 中华临床医师杂志(电子版), 2024, 18(08): 756-763.
[10] 陈秋怡, 林熙, 刘珍银. 淋巴管畸形分子机制的研究进展[J/OL]. 中华介入放射学电子杂志, 2024, 12(04): 374-379.
[11] 张成惠, 闫中瑞, 盛志强, 袁嫣然. 脑肌酸缺乏症诊断与治疗研究进展[J/OL]. 中华诊断学电子杂志, 2024, 12(04): 270-275.
[12] 胡瑞芳, 樊丽娟. 食管鳞状上皮内瘤变诊断的生物标志物研究进展及其非内镜治疗现状[J/OL]. 中华诊断学电子杂志, 2024, 12(04): 281-286.
[13] 张滕, 陶艳玲. Shwachman-Diamond综合征继发骨髓增生异常综合征一例及文献复习[J/OL]. 中华诊断学电子杂志, 2024, 12(03): 178-182.
[14] 徐来英, 程效, 戴亨纷, 侯俊凉, 苏怡林, 张彦. 药物联合个体化精准恒定功率运动疗法治疗心肌梗死术后频发室性早搏一例[J/OL]. 中华心脏与心律电子杂志, 2024, 12(03): 176-179.
[15] 李佳佳, 李凌华, 吕诗韵, 冯凯, 刘琳珊, 钟海丹, 颜婵, 刘聪. 广州市病毒学抑制失败HIV/AIDS患者的耐药特征及影响因素分析[J/OL]. 中华卫生应急电子杂志, 2024, 10(04): 207-212.
阅读次数
全文


摘要