Association between quasispecies variants of hepatitis B virus, as detected by high‑throughput sequencing, and progression of advanced liver disease in Indonesian patients

Putri,Wahyu  Aristyaning; Yano,Yoshihiko; Yamani,Laura  Navika; Liang,Yujiao; Mardian,Yan; Utsumi,Takako; Soetjipto,Soetjipto; Lusida,Maria  Inge; Hayashi,Yoshitake

doi:10.3892/mmr.2019.10250

July-2019 Volume 20 Issue 1

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July-2019 Volume 20 Issue 1

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Article

Association between quasispecies variants of hepatitis B virus, as detected by high‑throughput sequencing, and progression of advanced liver disease in Indonesian patients

Authors:
- Wahyu Aristyaning Putri
- Yoshihiko Yano
- Laura Navika Yamani
- Yujiao Liang
- Yan Mardian
- Takako Utsumi
- Soetjipto Soetjipto
- Maria Inge Lusida
- Yoshitake Hayashi
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Affiliations: Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan, Indonesia‑Japan Collaborative Research Centre for Emerging and Re‑emerging Infectious Disease, Institute of Tropical Disease, Airlangga University, Surabaya, East Java 60115, Indonesia, Division of Molecular Medicine and Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
Pages: 16-24
|
Published online on: May 16, 2019

https://doi.org/10.3892/mmr.2019.10250
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Abstract

Mutations in the hepatitis B virus (HBV) X region and truncation of the preS2 region are well‑known to affect the progression of liver disease. Recently, it has been observed that an increasing number of S region quasispecies variants are associated with disease progression. However, few studies have analysed quasispecies of the whole genome using high‑throughput sequencing methods. Using high‑throughput sequencing, whole‑genome variations in 12 Indonesian patients infected with HBV (eight with advanced liver disease and four with chronic hepatitis) were examined. Variations with cut‑off values of ≥1% of the total viral population were investigated. It was revealed that within the four open reading frames, quasispecies variations of the S and X regions were higher in advanced liver diseases compared with in chronic hepatitis (S region: 89.53 vs. 50.69%, P=0.047; X region: 76.95 vs. 35.88%, P=0.044). Notably, the mutation frequencies in the basal core promoter, B cell epitope, RT Box G, RNAseH and small S region were greater in advanced liver disease. The proportion of quasispecies variants increased for the majority of the mutations, with the exception for W196* in the small S gene, during disease progression. The present study demonstrated that quasispecies in the S and X regions of the HBV genome changed during disease progression and were associated with advanced liver disease development in Indonesian patients with HBV.

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1	Chen GF, Wang C and Lau G: Treatment of chronic hepatitis B infection-2017. Liver Int. 37 (Suppl 1):59–66. 2017. View Article : Google Scholar : PubMed/NCBI
2	Locarnini SA: Hepatitis B virus surface antigen and polymerase gene variants: potential virological and clinical significance. Hepatology. 27:294–297. 1998. View Article : Google Scholar : PubMed/NCBI
3	Heriyanto DS, Yano Y, Utsumi T, Anggorowati N, Rinonce HT, Lusida MI, Soetjipto, Triwikatmani C, Ratnasari N, Maduseno S, et al: Mutations within enhancer II and BCP regions of hepatitis B virus in relation to advanced liver diseases in patients infected with subgenotype B3 in Indonesia. J Med Virol. 84:44–51. 2012. View Article : Google Scholar : PubMed/NCBI
4	Zhu HL, Li X, Li J and Zhang ZH: Genetic variation of occult hepatitis B virus infection. World J Gastroenterol. 22:3531–3546. 2016. View Article : Google Scholar : PubMed/NCBI
5	Kendrick S and Day C: Natural history and factors influencing the course of alcohol-related liver disease. Clin Liver Dis. 2:61–63. 2013. View Article : Google Scholar
6	Luangsay S and Zoulim F: Structure and molecular virology. In: Viral hepatitis. 4th edition. Wiley-Blackwell; Hoboken, NJ: pp. 63–80. 2013
7	Gao S, Duan ZP and Coffin CS: Clinical relevance of hepatitis B virus variants. World J Hepatol. 7:1086–1096. 2015. View Article : Google Scholar : PubMed/NCBI
8	Rehermann B and Nascimbeni M: Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 5:215–229. 2005. View Article : Google Scholar : PubMed/NCBI
9	Yamani LN, Yano Y, Utsumi T, Juniastuti, Wandono H, Widjanarko D, Triantanoe A, Wasityastuti W, Liang Y, Okada R, et al: Ultradeep sequencing for detection of quasispecies variants in the major hydrophilic region of hepatitis b virus in Indonesian patients. J Clin Microbiol. 53:3165–3175. 2015. View Article : Google Scholar : PubMed/NCBI
10	Liao Y, Hu X, Chen J, Cai B, Tang J, Ying B, Wang H and Wang L: Precore mutation of hepatitis B virus may contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis. PLoS One. 7:e383942012. View Article : Google Scholar : PubMed/NCBI
11	Liang Y, Yano Y, Putri WA, Mardian Y, Okada R, Tanahashi T, Murakami Y and Hayashi Y: Early changes in quasispecies variant after antiviral therapy for chronic hepatitis B. Mol Med Rep. 17:5528–5537. 2018.PubMed/NCBI
12	Kim BK, Revill PA and Ahn SH: HBV genotypes: Relevance to natural history, pathogenesis and treatment of chronic hepatitis B. Antivir Ther. 16:1169–1186. 2011. View Article : Google Scholar : PubMed/NCBI
13	Huang CH, Yuan Q, Chen PJ, Zhang YL, Chen CR, Zheng QB, Yeh SH, Yu H, Xue Y, Chen YX, et al: Influence of mutations in hepatitis B virus surface protein on viral antigenicity and phenotype in occult HBV strains from blood donors. J Hepatol. 57:720–729. 2012. View Article : Google Scholar : PubMed/NCBI
14	Wilson JN, Nokes DJ and Carman WF: Current status of HBV vaccine escape variants-a mathematical model of their epidemiology. J Viral Hepat. 5 (Suppl 2):25–30. 1998. View Article : Google Scholar : PubMed/NCBI
15	Wasityastuti W, Yano Y, Widasari DI, Yamani LN, Ratnasari N, Heriyanto DS, Okada R, Tanahashi T, Murakami Y, Azuma T, et al: Different variants in reverse transcriptase domain determined by ultra-deep sequencing in treatment-naïve and treated indonesian patients infected with hepatitis B virus. Kobe J Med Sci. 62:E1–E8. 2016.PubMed/NCBI
16	Bobek V, Kolostova K, Pinterova D, Kacprzak G, Adamiak J, Kolodziej J, Boubelik M, Kubecova M and Hoffman RM: A clinically relevant, syngeneic model of spontaneous, highly metastatic B16 mouse melanoma. Anticancer Res. 30:4799–4803. 2010.PubMed/NCBI
17	Yano Y, Azuma T and Hayashi Y: Variations and mutations in the hepatitis B virus genome and their associations with clinical characteristics. World J Hepatol. 7:583–592. 2015. View Article : Google Scholar : PubMed/NCBI
18	An Introduction to Next-Generation Sequencing Technology, . Illumina, Inc.; San Diego, CA: 2015, https://www.illumina.com/documents/products/illumina_sequencing_introduction.pdf
19	Kim H, Lee SA, Do SY and Kim BJ: Precore/core region mutations of hepatitis B virus related to clinical severity. World J Gastroenterol. 22:4287–4296. 2016. View Article : Google Scholar : PubMed/NCBI
20	Kim H, Lee S and Kim BJ: X region mutations of hepatitis B virus related to clinical severity. World J Gastroenterol. 22:5467–5478. 2016. View Article : Google Scholar : PubMed/NCBI
21	Utama A, Purwantomo S, Siburian MD, Dhenni R, Gani RA, Hasan I, Sanityoso A, Miskad UA, Akil F, Yusuf I, et al: Hepatitis B virus subgenotypes and basal core promoter mutations in Indonesia. World J Gastroenterol. 15:4028–4036. 2009. View Article : Google Scholar : PubMed/NCBI
22	Utsumi T, Yano Y, Lusida MI, Amin M, Soetjipto, Hotta H and Hayashi Y: Serologic and molecular characteristics of hepatitis B virus among school children in East Java, Indonesia. Am J Trop Med Hyg. 83:189–193. 2010. View Article : Google Scholar : PubMed/NCBI
23	Mulyanto TF, Tsuda F, Karossi AT, Soewignjo S, Roestamsjah, Sumarsidi D, Trisnamurti RH, SumardiSurayah, Udin LZ, et al: Distribution of the hepatitis B surface antigen subtypes in Indonesia: Implications for ethnic heterogeneity and infection control measures. Arch Virol. 142:2121–2129. 1997. View Article : Google Scholar : PubMed/NCBI
24	Lamontagne RJ, Bagga S and Bouchard MJ: Hepatitis B virus molecular biology and pathogenesis. Hepatoma Res. 2:163–186. 2016. View Article : Google Scholar : PubMed/NCBI
25	Trépo C, Chan HLY and Lok A: Hepatitis B virus infection. Lancet. 384:2053–2063. 2014. View Article : Google Scholar : PubMed/NCBI
26	Capobianchi MR, Giombini E and Rozera G: Next-generation sequencing technology in clinical virology. Clin Microbiol Infect. 19:15–22. 2013. View Article : Google Scholar : PubMed/NCBI
27	Gong L, Han Y, Chen L, Liu F, Hao P, Sheng J, Li XH, Yu DM, Gong QM, Tian F, et al: Comparison of next-generation sequencing and clone-based sequencing in analysis of hepatitis B virus reverse transcriptase. J Clin Microbiol. 51:4087–4094. 2013. View Article : Google Scholar : PubMed/NCBI
28	Han Y, Gong L, Sheng J, Liu F, Li XH, Chen L, Yu DM, Gong QM, Hao P and Zhang XX: Prediction of virological response by pretreatment hepatitis B virus reverse transcriptase quasispecies heterogeneity: the advantage of using next-generation sequencing. Clin Microbiol Infect. 21:797.e1–8. 2015. View Article : Google Scholar
29	Solmone M, Vincenti D, Prosperi MCF, Bruselles A, Ippolito G and Capobianchi MR: Use of massively parallel ultradeep pyrosequencing to characterize the genetic diversity of hepatitis B virus in drug-resistant and drug-naive patients and to detect minor variants in reverse transcriptase and hepatitis B S antigen. J Virol. 83:1718–1726. 2009. View Article : Google Scholar : PubMed/NCBI
30	Du Y, Chi X, Wang C, Jiang J, Kong F, Yan H, Wang X, Li J, Wu NC, Dai L, et al: Quantifying perinatal transmission of Hepatitis B viral quasispecies by tag linkage deep sequencing. Sci Rep. 7:101682017. View Article : Google Scholar : PubMed/NCBI
31	Nishijima N, Marusawa H, Ueda Y, Takahashi K, Nasu A, Osaki Y, Kou T, Yazumi S, Fujiwara T, Tsuchiya S, et al: Dynamics of hepatitis B virus quasispecies in association with nucleos(t)ide analogue treatment determined by ultra-deep sequencing. PLoS One. 7:e350522012. View Article : Google Scholar : PubMed/NCBI
32	Fan C, Yang J and Engelhardt JF: Temporal pattern of NFkappaB activation influences apoptotic cell fate in a stimuli-dependent fashion. J Cell Sci. 115:4843–4853. 2002. View Article : Google Scholar : PubMed/NCBI
33	Mukherjee A, Choudhury M, Peruani F, Ganguly N and Mitra B: Dynamics on and of complex networks. 2 Birkhäuser; Basel: 2013
34	Shishodia S and Aggarwal BB: Nuclear factor-kappaB: A friend or a foe in cancer? Biochem Pharmacol. 68:1071–1080. 2004. View Article : Google Scholar : PubMed/NCBI
35	Zhang X and Ding H-G: Key role of hepatitis B virus mutation in chronic hepatitis B development to hepatocellular carcinoma. World J Hepatol. 7:1282–1286. 2015. View Article : Google Scholar : PubMed/NCBI
36	Tarocchi M, Polvani S, Marroncini G and Galli A: Molecular mechanism of hepatitis B virus-induced hepatocarcinogenesis. World J Gastroenterol. 20:11630–11640. 2014. View Article : Google Scholar : PubMed/NCBI
37	Badtke MP, Khan I, Cao F, Hu J and Tavis JE: An interdomain RNA binding site on the hepadnaviral polymerase that is essential for reverse transcription. Virology. 390:130–138. 2009. View Article : Google Scholar : PubMed/NCBI
38	Zhu B, Wang T, Wei X, Zhuo Y, Liu A and Zhang G: Accumulation of mutations in reverse transcriptase of hepatitis B virus is associated with liver disease severity in treatment-naïve Chinese patients with chronic hepatitis B. Adv Clin Exp Med. 26:1123–1129. 2017. View Article : Google Scholar : PubMed/NCBI
39	Tong S and Revill P: Overview of hepatitis B viral replication and genetic variability. J Hepatol. 64 (Suppl 1):S4–S16. 2016. View Article : Google Scholar : PubMed/NCBI
40	Rodriguez-Frias F, Buti M, Tabernero D and Homs M: Quasispecies structure, cornerstone of hepatitis B virus infection: Mass sequencing approach. World J Gastroenterol. 19:6995–7023. 2013. View Article : Google Scholar : PubMed/NCBI
41	Pacheco SR, Dos Santos MIMA, Stocker A, Zarife MAS, Schinoni MI, Paraná R, Dos Reis MG and Silva LK: Genotyping of HBV and tracking of resistance mutations in treatment-naïve patients with chronic hepatitis B. Infect Drug Resist. 10:201–207. 2017. View Article : Google Scholar : PubMed/NCBI
42	Shi YH and Shi CH: Molecular characteristics and stages of chronic hepatitis B virus infection. World J Gastroenterol. 15:3099–3105. 2009. View Article : Google Scholar : PubMed/NCBI
43	Khan A, Al Balwi MA, Tanaka Y, Hajeer A, Sanai FM, Al Abdulkarim I, Al Ayyar L, Badri M, Saudi D, Tamimi W, et al: Novel point mutations and mutational complexes in the enhancer II, core promoter and precore regions of hepatitis B virus genotype D1 associated with hepatocellular carcinoma in Saudi Arabia. Int J Cancer. 133:2864–2871. 2013.PubMed/NCBI
44	Asim M, Malik A, Sarma MP, Polipalli SK, Begum N, Ahmad I, Khan LA, Husain SA, Akhtar N, Husain S, et al: Hepatitis B virus BCP, Precore/core, X gene mutations/genotypes and the risk of hepatocellular carcinoma in India. J Med Virol. 82:1115–1125. 2010. View Article : Google Scholar : PubMed/NCBI
45	Clark DN and Hu J: Unveiling the roles of HBV polymerase for new antiviral strategies. Future Virol. 10:283–295. 2015. View Article : Google Scholar : PubMed/NCBI
46	Jones SA and Hu J: Hepatitis B virus reverse transcriptase: diverse functions as classical and emerging targets for antiviral intervention. Emerg Microbes Infect. 2:e562013. View Article : Google Scholar : PubMed/NCBI
47	Jones SA, Clark DN, Cao F, Tavis JE and Hu J: Comparative analysis of hepatitis B virus polymerase sequences required for viral RNA binding, RNA packaging, and protein priming. J Virol. 88:1564–1572. 2014. View Article : Google Scholar : PubMed/NCBI
48	Saha D, Pal A, Biswas A, Panigrahi R, Sarkar N, Das D, Sarkar J, Guha SK, Saha B, Chakrabarti S and Chakravarty R: Molecular characterization of HBV strains circulating among the treatment-naive HIV/HBV co-infected patients of eastern India. PLoS One. 9:e904322014. View Article : Google Scholar : PubMed/NCBI
49	Shi Y, Wei F, Hu D Li Q, Smith D, Li N and Chen D: Mutations in the major hydrophilic region (MHR) of hepatitis B virus genotype C in North China. J Med Virol. 84:1901–1906. 2012. View Article : Google Scholar : PubMed/NCBI
50	Juniastuti UT, Utsumi T, Aksono EB, Yano Y, Soetjipto, Hayashi Y, Hotta H, Rantam FA, Kusumobroto HO and Lusida MI: Predominance of precore mutations and clinical significance of basal core promoter mutations in chronic hepatitis B virus infection in Indonesia. Biomed Rep. 1:522–528. 2013. View Article : Google Scholar : PubMed/NCBI
51	Yang Z, Zhuang L, Lu Y, Xu Q, Tang B and Chen X: Naturally occurring basal core promoter A1762T/G1764A dual mutations increase the risk of HBV-related hepatocellular carcinoma: a meta-analysis. Oncotarget. 7:12525–12536. 2016.PubMed/NCBI