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

doi:10.3877/cma.j.issn.1674-1358.2018.04.017

Abstract

Abstract:

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.

Key words: Hepatitis B virus, Genotype, S gene, Drug treatment, Mutation

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]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2018, 12(04): 402-408.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhsyhlcgrbzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-1358.2018.04.017

https://zhsyhlcgrbzz.cma-cmc.com.cn/EN/Y2018/V12/I04/402

Figures/Tables 8

References 24

[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.

基因型	引物	序列号（5＇→3＇）	位点
ABCDE型	F	CCTGCTGGTGGCTCCAGTTC	nt55～74
ABCDE型	R	AAATGTATACCCAAAGACAAAAG	nt800～832
FGH型	F	TTCCTGCTGGTGGCTCCAGTTCAG	nt53～76
FH型	R	AATTGGTAACAGCGGTATAAAGGG	nt784～807
G型	R	GAGAAACGGACTGAGGCCCACTCCC	nt641～665

基因型	引物	序列号（5＇→3＇）	位点
ABCDE型	F	CCTGCTGGTGGCTCCAGTTC	nt55～74
ABCDE型	R	AAATGTATACCCAAAGACAAAAG	nt800～832
FGH型	F	TTCCTGCTGGTGGCTCCAGTTCAG	nt53～76
FH型	R	AATTGGTAACAGCGGTATAAAGGG	nt784～807
G型	R	GAGAAACGGACTGAGGCCCACTCCC	nt641～665

组别	例数	HBV DNA（× 10⁷ IU/ml）	AST（U/L）	ALT（U/L）
对照组	30	6.92 ± 3.85	46.21 ± 29.84	42.75 ± 19.13
干扰素治疗组	11	4.19 ± 2.38	162.33 ±18.47^b	95.10 ± 34.11
核苷酸类似物治疗组	14	2.45 ± 1.17^b	39.87 ± 17.18^a	40.50 ± 18.16
中成药治疗组	11	2.59 ± 0.96	84.83 ± 13.60	102.10 ± 52.13
保肝药治疗组	26	3.94 ± 1.14^b	86.34 ± 11.79^b	117.5 ± 12.83
t值	?	6.410	0.510	0.158
P值	?	0.003	2.394	2.112

组别	例数	HBV DNA（× 10⁷ IU/ml）	AST（U/L）	ALT（U/L）
对照组	30	6.92 ± 3.85	46.21 ± 29.84	42.75 ± 19.13
干扰素治疗组	11	4.19 ± 2.38	162.33 ±18.47^b	95.10 ± 34.11
核苷酸类似物治疗组	14	2.45 ± 1.17^b	39.87 ± 17.18^a	40.50 ± 18.16
中成药治疗组	11	2.59 ± 0.96	84.83 ± 13.60	102.10 ± 52.13
保肝药治疗组	26	3.94 ± 1.14^b	86.34 ± 11.79^b	117.5 ± 12.83
t值	?	6.410	0.510	0.158
P值	?	0.003	2.394	2.112

组别	例数	HBV DNA（× 10⁷ IU/ml）	AST（U/L）	ALT（U/L）
对照组	21	6.72 ± 2.85	44.71 ± 23.84	44.72 ± 17.23
干扰素治疗组	11	3.85 ± 1.74	55.30 ± 33.40	104.10 ± 42.57
核苷酸类似物治疗组	10	4.27 ± 1.25	91.20 ± 33.65	159.41 ± 52.72
中成药治疗组	11	7.11 ± 1.57	83.05 ± 37.92	75.75 ± 35.51
保肝药治疗组	10	3.33 ± 1.17	193.31 ± 11.08	113.5 ± 10.80
t值	?	0.435	2.123	3.113
P值	?	0.661	0.048	0.511

Please choose a citation manager

Content to export