Hepatitis B virus genetic variants: biological properties and clinical implications

Shuping TongLiver Research Center, Rhode Island Hospital, The Alpert Warren School of Medicine, Brown University, Providence, RI 02906, USA;Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaCorrespondence[email protected]

Jisu LiLiver Research Center, Rhode Island Hospital, The Alpert Warren School of Medicine, Brown University, Providence, RI 02906, USA

Jack R WandsLiver Research Center, Rhode Island Hospital, The Alpert Warren School of Medicine, Brown University, Providence, RI 02906, USA

Yu-mei WenKey Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China

Pages 1-11 | Received 05 Dec 2012, Accepted 04 Feb 2013, Published online: 25 Jan 2019

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https://doi.org/10.1038/emi.2013.10

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Ganem D, Prince AM.Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med2004;350:1118-1129.
PubMed Web of Science ®Google Scholar
Junker-Niepmann M, Bartenschlager R, Schaller H.A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA. EMBO J1990;9:3389-3396.
PubMed Web of Science ®Google Scholar
Garcia T, Li J, Sureau Cet al.Drastic reduction in the production of subviral particles does not impair hepatitis B virus virion secretion. J Virol2009;83:1152-11165.
PubMed Web of Science ®Google Scholar
Bruss V, Ganem D.The role of envelope proteins in hepatitis B virus assembly. Proc Natl Acad Sci USA1991;88:1059-1063.
PubMed Web of Science ®Google Scholar
Fernholz D, Galle PR, Stemler M, Brunetto M, Bonino F, Will H.Infectious hepatitis B virus variant defective in pre-S2 protein expression in a chronic carrier. Virology1993;194:137-148.
PubMed Web of Science ®Google Scholar
Ito K, Kim KH, Lok AS, Tong S.Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme. J Virol2009;83:3507-3517.
PubMed Web of Science ®Google Scholar
Ou JH, Laub O, Rutter WJ.Hepatitis B virus gene function: the precore region targets the core antigen to cellular membranes and causes the secretion of the e antigen. Proc Natl Acad Sci USA1986;83:1578-1582.
PubMed Web of Science ®Google Scholar
Messageot F, Salhi S, Eon P, Rossignol JM.Proteolytic processing of the hepatitis B virus e antigen precursor. Cleavage at two furin consensus sequences. J Biol Chem2003;278:891-895.
PubMed Web of Science ®Google Scholar
Norder H, Courouce AM, Coursaget Pet al.Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes. Intervirology2004;47:289-309.
PubMed Web of Science ®Google Scholar
Chu CJ, Lok AS.Clinical significance of hepatitis B virus genotypes. Hepatology2002;35:1274-1276.
PubMed Web of Science ®Google Scholar
Kramvis A, Arakawa K, Yu MC, Nogueira R, Stram DO, Kew MC.Relationship of serological subtype, basic core promoter and precore mutations to genotypes/subgenotypes of hepatitis B virus. J Med Virol2008;80:27-46.
PubMed Web of Science ®Google Scholar
Tanwar S, Dusheiko G.Is there any value to hepatitis B virus genotype analysis? Curr Gastroenterol Rep2012;14:37-46.
PubMedGoogle Scholar
Chang C, Enders G, Sprengel R, Peters N, Varmus HE, Ganem D.Expression of the precore region of an avian hepatitis B virus is not required for viral replication. J Virol1987;61:3322-3325.
PubMed Web of Science ®Google Scholar
Schlicht HJ, Salfeld J, Schaller H.The duck hepatitis B virus pre-C region encodes a signal sequence which is essential for synthesis and secretion of processed core proteins but not for virus formation. J Virol1987;61:3701-3709.
PubMed Web of Science ®Google Scholar
Brunetto MR, Stemler M, Bonino Fet al.A new hepatitis B virus strain in patients with severe anti-HBe positive chronic hepatitis B. J Hepatol1990;10:258-261.
PubMed Web of Science ®Google Scholar
Tong SP, Li JS, Vitvitski L, Trepo C.Active hepatitis B virus replication in the presence of anti-HBe is associated with viral variants containing an inactive pre-C region. Virology1990;176:596-603.
PubMed Web of Science ®Google Scholar
Carman WF, Jacyna MR, Hadziyannis Set al.Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet1989;2:588-591.
PubMed Web of Science ®Google Scholar
Okamoto H, Yotsumoto S, Akahane Yet al.Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen. J Virol1990;64:1298-1303.
PubMed Web of Science ®Google Scholar
Li J, Tong S, Vitvitski L, Zoulim F, Trepo C.Rapid detection and further characterization of infection with hepatitis B virus variants containing a stop codon in the distal pre-C region. J Gen Virol1990;71:1993-1998.
PubMed Web of Science ®Google Scholar
Chen HS, Kew MC, Hornbuckle WEet al.The precore gene of the woodchuck hepatitis virus genome is not essential for viral replication in the natural host. J Virol1992;66:5682-5684.
PubMed Web of Science ®Google Scholar
Cote PJ, Korba BE, Miller RHet al.Effects of age and viral determinants on chronicity as an outcome of experimental woodchuck hepatitis virus infection. Hepatology2000;31:190-200.
PubMed Web of Science ®Google Scholar
Kato H, Orito E, Gish RGet al.Hepatitis B e antigen in sera from individuals infected with hepatitis B virus of genotype G. Hepatology2002;35:922-929.
PubMed Web of Science ®Google Scholar
Milich DR, Schodel F, Hughes JL, Jones JE, Peterson DL.The hepatitis B virus core and e antigens elicit different Th cell subsets: antigen structure can affect Th cell phenotype. J Virol1997;71:2192-2201.
PubMed Web of Science ®Google Scholar
Milich DR, Jones JE, Hughes JL, Price J, Raney AK, McLachlan A.Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci USA1990;87:6599-6603.
PubMed Web of Science ®Google Scholar
Milich DR, Chen MK, Hughes JL, Jones JE.The secreted hepatitis B precore antigen can modulate the immune response to the nucleocapsid: a mechanism for persistence. J Immunol1998;160:2013-2021.
PubMed Web of Science ®Google Scholar
Chen MT, Billaud JN, Sallberg Met al.A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen. Proc Natl Acad Sci USA2004;101:14913-14918.
PubMed Web of Science ®Google Scholar
Tong SP, Li JS, Vitvitski L, Trepo C.Replication capacities of natural and artificial precore stop codon mutants of hepatitis B virus: relevance of pregenome encapsidation signal. Virology1992;191:237-245.
PubMed Web of Science ®Google Scholar
Tong SP, Li JS, Vitvitski L, Kay A, Treepo C.Evidence for a base-paired region of hepatitis B virus pregenome encapsidation signal which influences the patterns of precore mutations abolishing HBe protein expression. J Virol1993;67:5651-5655.
PubMed Web of Science ®Google Scholar
Li JS, Tong SP, Wen YM, Vitvitski L, Zhang Q, Trepo C.Hepatitis B virus genotype A rarely circulates as an HBe-minus mutant: possible contribution of a single nucleotide in the precore region. J Virol1993;67:5402-5410.
PubMed Web of Science ®Google Scholar
Lok AS, Akarca U, Greene S.Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci USA1994;91:4077-4081.
PubMed Web of Science ®Google Scholar
Chan HL, Tsui SK, Tse CHet al.Epidemiological and virological characteristics of 2 subgroups of hepatitis B virus genotype C. J Infect Dis2005;191:2022-2032.
PubMed Web of Science ®Google Scholar
Wang Z, Tanaka Y, Huang Yet al.Clinical and virological characteristics of hepatitis B virus subgenotypes Ba, C1, and C2 in China. J Clin Microbiol2007;45:1491-1496.
PubMed Web of Science ®Google Scholar
Yuan J, Zhou B, Tanaka Yet al.Hepatitis B virus (HBV) genotypes/subgenotypes in China: mutations in core promoter and precore/core and their clinical implications. J Clin Virol2007;39:87-93.
PubMed Web of Science ®Google Scholar
Alestig E, Hannoun C, Horal P, Lindh M.Phylogenetic origin of hepatitis B virus strains with precore C-1858 variant. J Clin Microbiol2001;39:3200-3203.
PubMed Web of Science ®Google Scholar
Arauz-Ruiz P, Norder H, Visona KA, Magnius LO.Genotype F prevails in HBV infected patients of hispanic origin in Central America and may carry the precore stop mutant. J Med Virol1997;51:305-312.
PubMed Web of Science ®Google Scholar
Norder H, Arauz-Ruiz P, Blitz L, Pujol FH, Echevarria JM, Magnius LO.The T(1858) variant predisposing to the precore stop mutation correlates with one of two major genotype F hepatitis B virus clades. J Gen Virol2003;84:2083-2087.
PubMed Web of Science ®Google Scholar
Okamoto H, Tsuda F, Akahane Yet al.Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol1994;68:8102-8110.
PubMed Web of Science ®Google Scholar
Buckwold VE, Xu Z, Chen M, Yen TS, Ou JH.Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J Virol1996;70:5845-5851.
PubMed Web of Science ®Google Scholar
Scaglioni PP, Melegari M, Wands JR.Biologic properties of hepatitis B viral genomes with mutations in the precore promoter and precore open reading frame. Virology1997;233:374-381.
PubMed Web of Science ®Google Scholar
Moriyama K, Okamoto H, Tsuda F, Mayumi M.Reduced precore transcription and enhanced core-pregenome transcription of hepatitis B virus DNA after replacement of the precore-core promoter with sequences associated with e antigen-seronegative persistent infections. Virology1996;226:269-280.
PubMed Web of Science ®Google Scholar
Tsai A, Kawai S, Kwei Ket al.Chimeric constructs between two hepatitis B virus genomes confirm transcriptional impact of core promoter mutations and reveal multiple effects of core gene mutations. Virology2009;387:364-372.
PubMed Web of Science ®Google Scholar
Guo X, Jin Y, Qian G, Tu H.Sequential accumulation of the mutations in core promoter of hepatitis B virus is associated with the development of hepatocellular carcinoma in Qidong, China. J Hepatol2008;49:718-725.
PubMed Web of Science ®Google Scholar
Tanaka Y, Hasegawa I, Kato Tet al.A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D. Hepatology2004;40:747-755.
PubMed Web of Science ®Google Scholar
Grabarczyk P, Garmiri P, Liszewski Get al.Molecular and serological characterization of hepatitis B virus genotype A and D infected blood donors in Poland. J Viral Hepat2010;17:444-452.
PubMed Web of Science ®Google Scholar
Orito E, Mizokami M, Sakugawa Het al.A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group. Hepatology2001;33:218-223.
PubMed Web of Science ®Google Scholar
Yuen MF, Sablon E, Yuan HJet al.Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion, cirrhosis-related complications, and hepatocellular carcinoma. Hepatology2003;37:562-567.
PubMed Web of Science ®Google Scholar
Lindh M, Hannoun C, Dhillon AP, Norkrans G, Horal P.Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers. J Infect Dis1999;179:775-782.
PubMed Web of Science ®Google Scholar
Qin Y, Tang X, Garcia Tet al.Hepatitis B virus genotype C isolates with wild-type core promoter sequence replicate less efficiently than genotype B isolates but possess higher virion secretion capacity. J Virol2011;85:10167-10177.
PubMed Web of Science ®Google Scholar
Nie J, Li J, Sun Ket al.HBV/D1: a major HBV subgenotype circulating in Uyghur patients with chronic HBV infection in Xinjiang, China. Arch Virol2012;157:1541-1549.
PubMed Web of Science ®Google Scholar
Inui A, Komatsu H, Sogo T, Nagai T, Abe K, Fujisawa T.Hepatitis B virus genotypes in children and adolescents in Japan: before and after immunization for the prevention of mother to infant transmission of hepatitis B virus. J Med Virol2007;79:670-675.
PubMed Web of Science ®Google Scholar
Coursaget P, Yvonnet B, Chotard Jet al.Age- and sex-related study of hepatitis B virus chronic carrier state in infants from an endemic area (Senegal). J Med Virol1987;22:1-5.
PubMed Web of Science ®Google Scholar
Jilbert A, Botten J, Miller Det al.Characterization of age and dose related outcomes of duck hepatitis B virus infection. Virology1998;244:273-282.
PubMed Web of Science ®Google Scholar
Hsia CC, Purcell RH, Farshid M, Lachenbruch PA, Yu MY.Quantification of hepatitis B virus genomes and infectivity in human serum samples. Transfusion2006;46:1829-1835.
PubMed Web of Science ®Google Scholar
Komiya Y, Katayama K, Yugi Het al.Minimum infectious dose of hepatitis B virus in chimpanzees and difference in the dynamics of viremia between genotype A and genotype C. Transfusion2008;48:286-294.
PubMed Web of Science ®Google Scholar
Asabe S, Wieland SF, Chattopadhyay PKet al.The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol2009;83:9652-9662.
PubMed Web of Science ®Google Scholar
Imamura T, Yokosuka O, Kurihara Tet al.Distribution of hepatitis B viral genotypes and mutations in the core promoter and precore regions in acute forms of liver disease in patients from Chiba, Japan. Gut2003;52:1630-1637.
PubMed Web of Science ®Google Scholar
Zhang HW, Yin JH, Li YTet al.Risk factors for acute hepatitis B and its progression to chronic hepatitis in Shanghai, China. Gut2008;57:1713-1720.
PubMed Web of Science ®Google Scholar
Matsuura K, Tanaka Y, Hige Set al.Distribution of hepatitis B virus genotypes among patients with chronic infection in Japan shifting toward an increase of genotype A. J Clin Microbiol 2009;47:1476-1483.
PubMed Web of Science ®Google Scholar
Suzuki Y, Kobayashi M, Ikeda Ket al.Persistence of acute infection with hepatitis B virus genotype A and treatment in Japan. J Med Virol2005;76:33-39.
PubMed Web of Science ®Google Scholar
Kobayashi M, Suzuki F, Arase Yet al.Infection with hepatitis B virus genotype A in Tokyo, Japan during 1976 through 2001. J Gastroenterol2004;39:844-850.
PubMed Web of Science ®Google Scholar
Mayerat C, Mantegani A, Frei PC.Does hepatitis B virus (HBV) genotype influence the clinical outcome of HBV infection? J Viral Hepat1999;6:299-304.
PubMed Web of Science ®Google Scholar
Rodriguez-Frias F, Jardi R, Buti Met al.Hepatitis B virus genotypes and G1896A precore mutation in 486 Spanish patients with acute and chronic HBV infection. J Viral Hepat2006;13:343-350.
PubMed Web of Science ®Google Scholar
Halfon P, Bourliere M, Pol Set al.Multicentre study of hepatitis B virus genotypes in France: correlation with liver fibrosis and hepatitis B e antigen status. J Viral Hepat2006;13:329-335.
PubMed Web of Science ®Google Scholar
Orito E, Ichida T, Sakugawa Het al.Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan. Hepatology2001;34:590-594.
PubMed Web of Science ®Google Scholar
Kao JH, Chen PJ, Lai MY, Chen DS.Hepatitis B virus genotypes and spontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis B carriers. J Med Virol2004;72:363-369.
PubMed Web of Science ®Google Scholar
Chu CJ, Hussain M, Lok AS.Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology2002;122:1756-1762.
PubMed Web of Science ®Google Scholar
Livingston SE, Simonetti JP, Bulkow LRet al.Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology2007;133:1452-1457.
PubMed Web of Science ®Google Scholar
Carman WF, Fagan EA, Hadziyannis Set al.Association of a precore genomic variant of hepatitis B virus with fulminant hepatitis. Hepatology1991;14:219-222.
PubMed Web of Science ®Google Scholar
Kosaka Y, Takase K, Kojima Met al.Fulminant hepatitis B: induction by hepatitis B virus mutants defective in the precore region and incapable of encoding e antigen. Gastroenterology1991;100:1087-1094.
PubMed Web of Science ®Google Scholar
Omata M, Ehata T, Yokosuka O, Hosoda K, Ohto M.Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. N Engl J Med1991;324:1699-1704.
PubMed Web of Science ®Google Scholar
Yotsumoto S, Kojima M, Shoji I, Yamamoto K, Okamoto H, Mishiro S.Fulminant hepatitis related to transmission of hepatitis B variants with precore mutations between spouses. Hepatology1992;16:31-35.
PubMed Web of Science ®Google Scholar
Sato S, Suzuki K, Akahane Yet al.Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med1995;122:241-248.
PubMed Web of Science ®Google Scholar
Friedt M, Gerner P, Lausch E, Trubel H, Zabel B, Wirth S.Mutations in the basic core promotor and the precore region of hepatitis B virus and their selection in children with fulminant and chronic hepatitis B. Hepatology 1999;29:1252-1258.
PubMed Web of Science ®Google Scholar
Hasegawa K, Huang J, Rogers SA, Blum HE, Liang TJ.Enhanced replication of a hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. J Virol1994;68:1651-1659.
PubMed Web of Science ®Google Scholar
Parekh S, Zoulim F, Ahn SHet al.Genome replication, virion secretion, and e antigen expression of naturally occurring hepatitis B virus core promoter mutants. J Virol2003;77:6601-6612.
PubMed Web of Science ®Google Scholar
Liang TJ, Hasegawa K, Rimon N, Wands JR, Ben-Porath E.A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med1991;324:1705-1709.
PubMed Web of Science ®Google Scholar
Baumert TF, Rogers SA, Hasegawa K, Liang TJ.Two core promotor mutations identified in a hepatitis B virus strain associated with fulminant hepatitis result in enhanced viral replication. J Clin Invest1996;98:2268-2276.
PubMed Web of Science ®Google Scholar
Stuyver L, De Gendt S, Cadranel JFet al.Three cases of severe subfulminant hepatitis in heart-transplanted patients after nosocomial transmission of a mutant hepatitis B virus. Hepatology1999;29:1876-1883.
PubMed Web of Science ®Google Scholar
Inoue J, Ueno Y, Nagasaki Fet al.Enhanced intracellular retention of a hepatitis B virus strain associated with fulminant hepatitis. Virology2009;395:202-209.
PubMed Web of Science ®Google Scholar
Nagasaki F, Ueno Y, Niitsuma Het al.Analysis of the entire nucleotide sequence of hepatitis B causing consecutive cases of fatal fulminant hepatitis in Miyagi Prefecture Japan. J Med Virol2008;80:967-973.
PubMed Web of Science ®Google Scholar
Arankalle VA, Gandhi S, Lole KS, Chadha MS, Gupte GM, Lokhande MU.An outbreak of hepatitis B with high mortality in India: association with precore, basal core promoter mutants and improperly sterilized syringes. J Viral Hepat2011;18:e20-28.
PubMed Web of Science ®Google Scholar
McMillan JS, Bowden DS, Angus PW, McCaughan GW, Locarnini SA.Mutations in the hepatitis B virus precore/core gene and core promoter in patients with severe recurrent disease following liver transplantation. Hepatology1996;24:1371-1378.
PubMed Web of Science ®Google Scholar
Ozasa A, Tanaka Y, Orito Eet al.Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology2006;44:326-334.
PubMed Web of Science ®Google Scholar
Ren X, Xu Z, Liu Yet al.Hepatitis B virus genotype and basal core promoter/precore mutations are associated with hepatitis B-related acute-on-chronic liver failure without pre-existing liver cirrhosis. J Viral Hepat2010;17:887-895.
PubMed Web of Science ®Google Scholar
Huang SN, Chisari FV.Strong, sustained hepatocellular proliferation precedes hepatocarcinogenesis in hepatitis B surface antigen transgenic mice. Hepatology1995;21:620-626.
PubMed Web of Science ®Google Scholar
Yang HI, Lu SN, Yun-Fan liaw SLYet al.Hepatitis B e Antigen and the Risk of Hepatocellular Carcinoma. New Engl J Med2002;347:168-173.
PubMed Web of Science ®Google Scholar
Ishikawa T, Ichida T, Yamagiwa Set al.High viral loads, serum alanine aminotransferase and gender are predictive factors for the development of hepatocellular carcinoma from viral compensated liver cirrhosis. J Gastroenterol Hepatol2001;16:1274-1281.
PubMed Web of Science ®Google Scholar
Ohata K, Hamasaki K, Toriyama K, Ishikawa H, Nakao K, Eguchi K.High viral load is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Gastroenterol Hepatol2004;19:670-675.
PubMed Web of Science ®Google Scholar
Tang B, Kruger WD, Chen Get al.Hepatitis B viremia is associated with increased risk of hepatocellular carcinoma in chronic carriers. J Med Virol2004;72:35-40.
PubMed Web of Science ®Google Scholar
Yu MW, Yeh SH, Chen PJet al.Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst2005;97:265-272.
PubMed Web of Science ®Google Scholar
Wu CF, Yu MW, Lin CLet al.Long-term tracking of hepatitis B viral load and the relationship with risk for hepatocellular carcinoma in men. Carcinogenesis2008;29: 106-112.
PubMed Web of Science ®Google Scholar
Chen CJ, Yang HI, Su Jet al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA2006;295:65-73.
PubMed Web of Science ®Google Scholar
Kew MC, Kramvis A, Yu MC, Arakawa K, Hodkinson J.Increased hepatocarcinogenic potential of hepatitis B virus genotype A in Bantu-speaking sub-saharan Africans. J Med Virol2005;75:513-521.
PubMed Web of Science ®Google Scholar
Thakur V, Guptan RC, Kazim SN, Malhotra V, Sarin SK.Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent. J Gastroenterol Hepatol2002;17:165-170.
PubMed Web of Science ®Google Scholar
Madan K, Batra Y, Sreenivas Vet al.HBV genotypes in India: do they influence disease severity? Hepatol Res2009;39:157-163.
PubMed Web of Science ®Google Scholar
Asim M, Malik A, Sarma MPet al.Hepatitis B virus BCP, Precore/core, X gene mutations/genotypes and the risk of hepatocellular carcinoma in India. J Med Virol2010;82:1115-1125.
PubMed Web of Science ®Google Scholar
Livingston SE, Simonetti JP, McMahon BJet al.Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F. J Infect Dis 2007;195:5-11.
PubMed Web of Science ®Google Scholar
Kao JH, Chen PJ, Lai MY, Chen DS.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000;118:554-559.
PubMed Web of Science ®Google Scholar
Chu CM, Liaw YF.Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline. J Hepatol2005;43:411-417.
PubMed Web of Science ®Google Scholar
Sumi H, Yokosuka O, Seki Net al.Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology2003;37:19-26.
PubMed Web of Science ®Google Scholar
Sugauchi F, Orito E, Ichida Tet al.Hepatitis B virus of genotype B with or without recombination with genotype C over the precore region plus the core gene. J Virol2002;76:5985-5992.
PubMed Web of Science ®Google Scholar
Yuen MF, Tanaka Y, Mizokami Met al.Role of hepatitis B virus genotypes Ba and C, core promoter and precore mutations on hepatocellular carcinoma: a case control study. Carcinogenesis2004;25:1593-1598.
PubMed Web of Science ®Google Scholar
Chan HL, Hui AY, Wong MLet al.Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut2004;53:1494-1498.
PubMed Web of Science ®Google Scholar
Liu S, Xie J, Yin Jet al.A matched case-control study of hepatitis B virus mutations in the preS and core promoter regions associated independently with hepatocellular carcinoma. J Med Virol2011;83:45-53.
PubMed Web of Science ®Google Scholar
Hsia CC, Yuwen H, Tabor E.Hot-spot mutations in hepatitis B virus X gene in hepatocellular carcinoma. Lancet1996;348:625-626.
PubMed Web of Science ®Google Scholar
Takahashi K, Akahane Y, Hino K, Ohta Y, Mishiro S.Hepatitis B virus genomic sequence in the circulation of hepatocellular carcinoma patients: comparative analysis of 40 full-length isolates. Arch Virol1998;143:2313-2326.
PubMed Web of Science ®Google Scholar
Baptista M, Kramvis A, Kew MC.High prevalence of 1762(T) 1764(A) mutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers. Hepatology1999;29:946-953.
PubMed Web of Science ®Google Scholar
Kao JH, Chen PJ, Lai MY, Chen DS.Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology2003;124:327-334.
PubMed Web of Science ®Google Scholar
Kuang SY, Jackson PE, Wang JBet al.Specific mutations of hepatitis B virus in plasma predict liver cancer development. Proc Natl Acad Sci USA2004;101:3575-3580.
PubMed Web of Science ®Google Scholar
Chou YC, Yu MW, Wu CFet al.Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma. Gut2008;57:91-97.
PubMed Web of Science ®Google Scholar
Yuen MF, Tanaka Y, Fong DYet al.Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol2009;50:80-88.
PubMed Web of Science ®Google Scholar
Chan HL, Hussain M, Lok AS.Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology1999;29:976-984.
PubMed Web of Science ®Google Scholar
Tanaka Y, Mukaide M, Orito Eet al.Specific mutations in enhancer II/core promoter of hepatitis B virus subgenotypes C1/C2 increase the risk of hepatocellular carcinoma. J Hepatol2006;45:646-653.
PubMed Web of Science ®Google Scholar
Takahashi K, Ohta Y, Kanai Ket al.Clinical implications of mutations C-to-T1653 and T-to-C/A/G1753 of hepatitis B virus genotype C genome in chronic liver disease. Arch Virol1999;144:1299-1308.
PubMed Web of Science ®Google Scholar
Shinkai N, Tanaka Y, Ito Ket al.Influence of hepatitis B virus X and core promoter mutations on hepatocellular carcinoma among patients infected with subgenotype C2. J Clin Microbiol2007;45:3191-3197.
PubMed Web of Science ®Google Scholar
Yuen MF, Tanaka Y, Shinkai Net al.Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels. Gut2008;57:98-102.
PubMed Web of Science ®Google Scholar
Ito K, Tanaka Y, Orito Eet al.T1653 mutation in the box alpha increases the risk of hepatocellular carcinoma in patients with chronic hepatitis B virus genotype C infection. Clin Infect Dis2006;42:1-7.
PubMed Web of Science ®Google Scholar
Chen CH, Hung CH, Lee CMet al.Pre-S deletion and complex mutations of hepatitis B virus related to advanced liver disease in HBeAg-negative patients. Gastroenterology2007;133:1466-1474.
PubMed Web of Science ®Google Scholar
Ma NF, Lau SH, Hu Let al.COOH-terminal truncated HBV X protein plays key role in hepatocarcinogenesis. Clin Cancer Res2008;14:5061-5068.
PubMed Web of Science ®Google Scholar
Tu H, Bonura C, Giannini Cet al.Biological impact of natural COOH-terminal deletions of hepatitis B virus X protein in hepatocellular carcinoma tissues. Cancer Res2001;61:7803-7810.
PubMed Web of Science ®Google Scholar
Sirma H, Giannini C, Poussin K, Paterlini P, Kremsdorf D, Brechot C.Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx. Oncogene1999;18:4848-4859.
PubMed Web of Science ®Google Scholar
Kwun HJ, Jang KL.Natural variants of hepatitis B virus X protein have differential effects on the expression of cyclin-dependent kinase inhibitor p21 gene. Nucleic Acids Res2004;32:2202-2213.
PubMed Web of Science ®Google Scholar
Huang Y, Tong S, Tai AW, Hussain M, Lok AS.Hepatitis B virus core promoter mutations contribute to hepatocarcinogenesis by deregulating SKP2 and its target, p21. Gastroenterology2012;141:1412-1421.
Web of Science ®Google Scholar
Fang ZL, Sabin CA, Dong BQet al.Hepatitis B virus pre-S deletion mutations are a risk factor for hepatocellular carcinoma: a matched nested case-control study. J Gen Virol2008;89:2882-2890.
PubMed Web of Science ®Google Scholar
Chen CH, Changchien CS, Lee CMet al.Combined mutations in pre-s/surface and core promoter/precore regions of hepatitis B virus increase the risk of hepatocellular carcinoma: a case-control study. J Infect Dis2008;198:1634-1642.
PubMed Web of Science ®Google Scholar
Huy TT, Ushijima H, Win KMet al.High prevalence of hepatitis B virus pre-s mutant in countries where it is endemic and its relationship with genotype and chronicity. J Clin Microbiol2003;41:5449-5455.
PubMed Web of Science ®Google Scholar
Chen BF, Liu CJ, Jow GM, Chen PJ, Kao JH, Chen DS.High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases. Gastroenterology2006;130:1153-1168.
PubMed Web of Science ®Google Scholar
Sugauchi F, Ohno T, Orito Eet al.Influence of hepatitis B virus genotypes on the development of preS deletions and advanced liver disease. J Med Virol2003;70:537-544.
PubMed Web of Science ®Google Scholar
Huang HP, Hsu HY, Chen CLet al.Pre-S2 deletions of hepatitis B virus and hepatocellular carcinoma in children. Pediatr Res2010;67:90-94.
PubMed Web of Science ®Google Scholar
Abe K, Thung SN, Wu HCet al.Pre-S2 deletion mutants of hepatitis B virus could have an important role in hepatocarcinogenesis in Asian children. Cancer Sci2009;100:2249-2254.
PubMed Web of Science ®Google Scholar
Wang HC, Wu HC, Chen CF, Fausto N, Lei HY, Su IJ.Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress. Am J Pathol2003;163:2441-2449.
PubMed Web of Science ®Google Scholar
Hsieh YH, Su IJ, Wang HCet al.Pre-S mutant surface antigens in chroic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis2004;25:2023-2032.
PubMed Web of Science ®Google Scholar
Hsieh YH, Su IJ, Wang HCet al.Hepatitis B Virus Pre-S2 Mutant Surface Antigen Induces Degradation of Cyclin-Dependent Kinase Inhibitor p27Kip1 through c-Jun Activation Domain-Binding Protein 1. Mol Cancer Res2007;5:1063-1072.
PubMed Web of Science ®Google Scholar
Wang HC, Chang WT, Chang WWet al.Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes. Hepatology2005;41:761-770.
PubMed Web of Science ®Google Scholar
Gish R, Jia JD, Locarnini S, Zoulim F.Selection of chronic hepatitis B therapy with high barrier to resistance. Lancet Infect Dis2012;12:341-353.
PubMed Web of Science ®Google Scholar
Zoulim F, Locarnini S.Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology2009;137:1593-1608.
PubMed Web of Science ®Google Scholar
Warner N, Locarnini S.The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound. Hepatology2008;48:88-98.
PubMed Web of Science ®Google Scholar
Lai MW, Yeh CT.The oncogenic potential of hepatitis B virus rtA181T/surface truncation mutant. Antivir Ther2008;13:875-879.
PubMed Web of Science ®Google Scholar
Wen WH, Chen HL, Ni YHet al.Secular trend of the viral genotype distribution in children with chronic hepatitis B virus infection after universal infant immunization. Hepatology2011;53:429-436.
PubMed Web of Science ®Google Scholar
Shao ZJ, Zhang L, Xu JQet al.Mother-to-infant transmission of hepatitis B virus: A Chinese experience. J Med Virol2011;83:791-795.
PubMed Web of Science ®Google Scholar
Carman WF, Zanetti AR, Karayiannis Pet al.Vaccine-induced escape mutant of hepatitis B virus. Lancet1990;336:325-329.
PubMed Web of Science ®Google Scholar
Harrison TJ, Hopes EA, Oon CJ, Zanetti AR, Zuckerman AJ.Independent emergence of a vaccine-induced escape mutant of hepatitis B virus. J Hepatol1991;13Suppl 4 105-107.
Web of Science ®Google Scholar
Karthigesu VD, Allison LM, Fortuin M, Mendy M, Whittle HC, Howard CR.A novel hepatitis B virus variant in the sera of immunized children. J Gen Virol1994;75:443-448.
PubMed Web of Science ®Google Scholar
McMahon G, Ehrlich PH, Moustafa ZAet al.Genetic alterations in the gene encoding the major HBsAg: DNA and immunological analysis of recurrent HBsAg derived from monoclonal antibody-treated liver transplant patients. Hepatology1992;15:757-766.
PubMed Web of Science ®Google Scholar
Carman WF, Trautwein C, van Deursen FJet al.Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis. Hepatology1996;24:489-493.
PubMed Web of Science ®Google Scholar
Ghany MG, Ayola B, Villamil FGet al.Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis. Hepatology1998;27:213-222.
PubMed Web of Science ®Google Scholar
Protzer-Knolle U, Naumann U, Bartenschlager Ret al.Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation. Hepatology1998;27:254-263.
PubMed Web of Science ®Google Scholar
Waters JA, Kennedy M, Voet Pet al.Loss of the common "A" determinant of hepatitis B surface antigen by a vaccine-induced escape mutant. J Clin Invest1992;90:2543-2547.
PubMed Web of Science ®Google Scholar
Cooreman MP, van Roosmalen MH, te Morsche Ret al.Characterization of the reactivity pattern of murine monoclonal antibodies against wild-type hepatitis B surface antigen to G145R and other naturally occurring "a" loop escape mutations. Hepatology1999;30:1287-1292.
PubMed Web of Science ®Google Scholar
Chiou HL, Lee TS, Kuo J, Mau YC, Ho MS.Altered antigenicity of 'a' determinant variants of hepatitis B virus. J Gen Virol1997;78:2639-2645.
PubMed Web of Science ®Google Scholar
Hsu HY, Chang MH, Ni YH, Chen HL.Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan. Gut2004;53:1499-1503.
PubMed Web of Science ®Google Scholar
Hsu HY, Chang MH, Ni YHet al.No increase in prevalence of hepatitis B surface antigen mutant in a population of children and adolescents who were fully covered by universal infant immunization. J Infect Dis2010;201:1192-1200.
PubMed Web of Science ®Google Scholar
Kalinina T, Iwanski A, Will H, Sterneck M.Deficiency in virion secretion and decreased stability of the hepatitis B virus immune escape mutant G145R. Hepatology2003;38:1274-1281.
PubMed Web of Science ®Google Scholar
Ito K, Qin Y, Guarnieri Met al.Impairment of hepatitis B virus virion secretion by single-amino-acid substitutions in the small envelope protein and rescue by a novel glycosylation site. J Virol2010;84:12850-12861.
PubMed Web of Science ®Google Scholar
Huang CH, Yuan Q, Chen PJet al.Influence of mutations in hepatitis B virus surface protein on viral antigenicity and phenotype in occult HBV strains from blood donors. J Hepatol2012;57:720-729.
PubMed Web of Science ®Google Scholar
Kwei K, Tang X, Lok ASet al.Impaired virion secretion by hepatitis B virus immune escape mutants and its rescue by wild-type envelope proteins or a second-site mutation. J Virol2013;87:2352-2357.
PubMed Web of Science ®Google Scholar
Le Duff Y, Blanchet M, Sureau C.The pre-S1 and antigenic loop infectivity determinants of the hepatitis B virus envelope proteins are functionally independent. J Virol2009;83:12443-12451.
PubMed Web of Science ®Google Scholar
Salisse J, Sureau C.A function essential to viral entry underlies the hepatitis B virus "a" determinant. J Virol2009;83:9321-9328.
PubMed Web of Science ®Google Scholar
Raimondo G, Pollicino T, Cacciola I, Squadrito G.Occult hepatitis B virus infection. J Hepatol2007;46:160-170.
PubMed Web of Science ®Google Scholar
Samal J, Kandpal M, Vivekanandan P.Molecular mechanisms underlying occult hepatitis B virus infection. Clin Microbiol Rev2012;25:142-163.
PubMed Web of Science ®Google Scholar

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