The immune response to hepatitis B virus (HBV) is important for both viral control and disease pathogenesis. A detailed understanding of the HBV-specific T-cell responses may potentially lead to novel therapeutic strategies for HBV.
Methods
All English language journal articles (including articles in press) up to October 2007 were retrieved using searches of MEDLINE, EMBASE and the Cochrane Controlled Trial Registry. An extensive database of HBV sequences (SeqHepB) and GenBank were used to assess the degree of sequence variation in each epitope. The new standardized nomenclature for HBV amino acid position number was applied to all previously defined epitopes.
Results
Forty-four HBV-specific human leukocyte antigen (HLA) class I restricted and 32 HBV-specific HLA class II restricted epitopes have been defined and have been identified in all HBV genes. The majority of HLA class I restricted epitopes have been defined in HLA-A2-positive individuals in the setting of acute HBV infection. There is significant sequence variation of these epitopes within and between HBV genotypes. Newer HBV immunotherapeutics appear promising but are still in early phases of development.
Conclusions
Identification of HBV-specific epitopes in non-HLA-A2-positive individuals and recognition of genotypic variation across epitopes are important for the future development of novel immunotherapeutic strategies for the management of chronic HBV infection.
References
1.
SimmondsP., MidgleyS.Recombination in the genesis and evolution of hepatitis B virus genotypes.J Virol2005; 79: 15467–15476.
2.
SobaoY., SugiK., TomiyamaH.Identification of hepatitis B virus-specific CTL epitopes presented by HLA-A*2402, the most common HLA class I allele in East Asia.J Hepatol2001; 34: 922–929.
3.
ChisariF.V., FerrariC.Hepatitis B virus immunopathogenesis.Annu Rev Immunol1995; 13: 29–60.
4.
ChangJ.J., LewinS.R.Immunopathogenesis of hepatitis B virus infection.Immunol Cell Biol2007; 85: 16–23.
5.
StuyverL.J., LocarniniS.A., LokA.Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region.Hepatology2001; 33: 751–757.
6.
Cochrane Library. Cochrane Database of Systematic Reviews2007. (Updated October 2007. Accessed October 2007). Available from http://www.cochrane.org.
7.
YuenL.K., AyresA., LittlejohnM.SeqHepB: a sequence analysis program and relational database system for chronic hepatitis B.Antivir Res2007; 75: 64–74.
8.
ScaglioniP.P., MelegariM., WandsJ.R.Recent advances in the molecular biology of hepatitis B virus.Baillieres Clin Gastroenterol1996; 10: 207–225.
9.
NowakM.A., BonhoefferS., HillA.M., BoehmeR., ThomasH.C., McDadeH.Viral dynamics in hepatitis B virus infection.Proc Natl Acad Sci U S A1996; 93: 4398–4402.
10.
LewinS.R., RibeiroR.M., WaltersT.Analysis of hepatitis B viral load decline under potent therapy: complex decay profiles observed.Hepatology2001; 34: 1012–1020.
11.
OritoE., MizokamiM., InaY.Host-independent evolution and a genetic classification of the hepadnavirus family based on nucleotide sequences.Proc Natl Acad Sci U S A1989; 86: 7059–7062.
12.
OgataN., AlterH.J., MillerR.H., PurcellR.H.Nucleotide sequence and mutation rate of the H strain of hepatitis C virus.Proc Natl Acad Sci U S A1991; 88: 3392–3396.
13.
KatoN., NakamuraT., DansakoH.Genetic variation and dynamics of hepatitis C virus replicons in long-term cell culture.J Gen Virol2005; 86: 645–656.
14.
LeitnerT., AlbertJ.The molecular clock of HIV-1 unveiled through analysis of a known transmission history.Proc Natl Acad Sci U S A1999; 96: 10752–10757.
15.
LinC.L., TsaiS.L., LeeT.H., ChienR.N., LiaoS.K., LiawY.F.High frequency of functional anti-YMDD and -mutant cytotoxic T lymphocytes after in vitro expansion correlates with successful response to lamivudine therapy for chronic hepatitis B.Gut2005; 54: 152–161.
16.
HannounC., HoralP., LindhM.Long-term mutation rates in the hepatitis B virus genome.J Gen Virol2000; 81: 75–83.
17.
OsiowyC., GilesE., TanakaY., MizokamiM., MinukG.Y.Molecular Evolution of Hepatitis B Virus over 25 Years.J Virol2006; 80: 10307–10314.
18.
DomingoE., MartinV., PeralesC., Grande-PerezA., Garcia-ArriazaJ., AriasA.Viruses as quasispecies: biological implications.Curr Top Microbiol Immunol2006; 299: 51–82.
19.
NorderH., CourouceA.M., MagniusL.O.Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes.Virology1994; 198: 489–503.
20.
StuyverL., De GendtS., Van GeytC.A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness.J Gen Virol2000; 81: 67–74.
21.
Arauz-RuizP., NorderH., RobertsonB.H., MagniusL.O.Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America.J Gen Virol2002; 83: 2059–2073.
22.
KramvisA., KewM., FrancoisG.Hepatitis B virus genotypes.Vaccine2005; 23: 2409–2423.
23.
BowyerS.M., van StadenL., KewM.C., SimJ.G.A unique segment of the hepatitis B virus group A genotype identified in isolates from South Africa.J Gen Virol1997; 78: 1719–1729.
24.
SugauchiF., OritoE., IchidaT.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.
25.
HuyT.T., UshijimaH., QuangV.X.Genotype C of hepatitis B virus can be classified into at least two subgroups.J Gen Virol2004; 85: 283–292.
26.
MbayedV.A., BarbiniL., LopezJ.L., CamposR.H.Phylogenetic analysis of the hepatitis B virus (HBV) genotype F including Argentine isolates.Arch Virol2001; 146: 1803–1810.
27.
NorderH., HammasB., LeeS.D.Genetic relatedness of hepatitis B viral strains of diverse geographical origin and natural variations in the primary structure of the surface antigen.J Gen Virol1993; 74: 1341–1348.
28.
LindhM., AnderssonA.S., GusdalA.Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus – large-scale analysis using a new genotyping method.J Infect Dis1997; 175: 1285–1293.
29.
MorozovV., PisarevaM., GroudininM.Homologous recombination between different genotypes of hepatitis B virus.Gene2000; 260: 55–65.
30.
WangZ., LiuZ., ZengG.A new intertype recombinant between genotypes C and D of hepatitis B virus identified in China.J Gen Virol2005; 86: 985–990.
31.
ShiinaS., FujinoH., UtaY.Relationship of HBsAg subtypes with HBeAg/anti-HBe status and chronic liver disease. Part I: Analysis of 1744 HBsAg carriers.Am J Gastroenterol1991; 86: 866–871.
32.
LindhM., HannounC., DhillonA.P., NorkransG., HoralP.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.
33.
KaoJ.H., ChenP.J., LaiM.Y., ChenD.S.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.Gastroenterology2000; 118: 554–559.
34.
ChuC.M., LiawY F.. 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.
35.
SumiH., YokosukaO., SekiN.Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease.Hepatology2003; 37: 19–26.
36.
OritoE., MizokamiM., SakugawaH.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.
37.
KobayashiM., AraseY., IkedaK.Clinical features of hepatitis B virus genotype A in Japanese patients.J Gastroenterol2003; 38: 656–662.
38.
SuzukiY., KobayashiM., IkedaK.Persistence of acute infection with hepatitis B virus genotype A and treatment in Japan.J Med Virol2005; 76: 33–39.
39.
MayeratC., ManteganiA., FreiP.C.Does hepatitis B virus (HBV) genotype influence the clinical outcome of HBV infection?J Viral Hepat1999; 6: 299–304.
40.
ChuC.J., HussainM., LokA.S.Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C.Gastroenterology2002; 122: 1756–1762.
41.
YuenM.F., SablonE., YuanH.J.Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion, cirrhosis-related complications, and hepatocellular carcinoma.Hepatology2003; 37: 562–567.
42.
NakayoshiT., MaeshiroT., NakayoshiT.Difference in prognosis between patients infected with hepatitis B virus with genotype B and those with genotype C in the Okinawa Islands: a prospective study.J Med Virol2003; 70: 350–354.
43.
KaoJ.H., ChenP.J., LaiM.Y., ChenD.S.Hepatitis B virus genotypes and spontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis B carriers.J Med Virol2004; 72: 363–369.
44.
NiY.H., ChangM.H., WangK.J.Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma.Gastroenterology2004; 127: 1733–1738.
45.
WaiC.T., ChuC.J., HussainM., LokA.S.HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C.Hepatology2002; 36: 1425–1430.
46.
LiJ.S., TongS.P., WenY.M., VitvitskiL., ZhangQ., TrepoC.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.
47.
Rodriguez-FriasF., ButiM., JardiR.Hepatitis B virus infection: precore mutants and its relation to viral genotypes and core mutations.Hepatology1995; 22: 1641–1647.
48.
HussainM., ChuC.J., SablonE., LokA.S.Rapid and sensitive assays for determination of hepatitis B virus (HBV) genotypes and detection of HBV precore and core promoter variants.J Clin Microbiol2003; 41: 3699–3705.
49.
ErhardtA., BlondinD., HauckK.Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D.Gut2005; 54: 1009–1013.
50.
JanssenH.L., van ZonneveldM., SenturkH.Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.Lancet2005; 365: 123–129.
51.
KewM.C., KramvisA., YuM.C., ArakawaK., HodkinsonJ.Increased hepatocarcinogenic potential of hepatitis B virus genotype A in Bantu-speaking sub-saharan Africans.J Med Virol2005; 75: 513–521.
52.
LiebermanH.M., LaBrecqueD.R., KewM.C., HadziyannisS.J., ShafritzD.A.Detection of hepatitis B virus DNA directly in human serum by a simplified molecular hybridization test: comparison to HBeAg/anti-HBe status in HBsAg carriers.Hepatology1983; 3: 285–291.
53.
SongE., DusheikoG.M., BowyerS., KewM.C.Hepatitis B virus replication in southern Africa blacks with HBsAg-positive hepatocellular carcinoma.Hepatology1984; 4: 608–610.
54.
ParkerD.C.T cell-dependent B cell activation.Annu Rev Immunol1993; 11: 331–360.
55.
YewdellJ.W., BenninkJ.R.Cell biology of antigen processing and presentation to major histocompatibility complex class I molecule-restricted T lymphocytes.Adv Immunol1992; 52: 1–123.
56.
VitettaE.S., Fernandez-BotranR., MyersC.D., SandersV.M.Cellular interactions in the humoral immune response.Adv Immunol1989; 45: 1–105.
57.
DohertyP.C., AllanW., EichelbergerM., CardingS.R.Roles of alpha beta and gamma delta T cell subsets in viral immunity.Annu Rev Immunol1992; 10: 123–151.
58.
MainiM.K., BertolettiA.How can the cellular immune response control hepatitis B virus replication?J Viral Hepat2000; 7: 321–326.
59.
BarnabaV., FrancoA., AlbertiA., BalsanoC., BenvenutoR., BalsanoF.Recognition of hepatitis B virus envelope proteins by liver-infiltrating T lymphocytes in chronic HBV infection.J Immunol1989; 143: 2650–2655.
60.
FerrariC., BertolettiA., PennaA.Identification of immunodominant T cell epitopes of the hepatitis B virus nucleocapsid antigen.J Clin Invest1991; 88: 214–222.
61.
BertolettiA., FerrariC., FiaccadoriF.HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen.Proc Natl Acad Sci U S A1991; 88: 10445–10449.
62.
PennaA., ChisariF.V., BertolettiA.Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen.J Exp Med1991; 174: 1565–1570.
63.
NayersinaR., FowlerP., GuilhotS.HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection.J Immunol1993; 150: 4659–4671.
64.
BertoniR., SidneyJ., FowlerP., ChesnutR.W., ChisariF.V., SetteA.Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis.J Clin Invest1997; 100: 503–513.
65.
LeeW.M.Hepatitis B virus infection.N Engl J Med1997; 337: 1733–1745.
66.
HwangY.K., KimN.K., ParkJ.M.HLA-A2 1 restricted peptides from the HBx antigen induce specific CTL responses in vitro and in vivo.Vaccine2002; 20: 3770–3777.
67.
RehermannB., FowlerP., SidneyJ.The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis.J Exp Med1995; 181: 1047–1058.
68.
MissaleG., RedekerA., PersonJ.HLA-A31- and HLA-Aw68-restricted cytotoxic T cell responses to a single hepatitis B virus nucleocapsid epitope during acute viral hepatitis.J Exp Med1993; 177: 751–762.
69.
MizukoshiE., SidneyJ., LivingstonB.Cellular immune responses to the hepatitis B virus polymerase.J Immunol2004; 173: 5863–5871.
70.
SetteA., VitielloA., RehermanB.The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes.J Immunol1994; 153: 5586–5592.
71.
LetschA., ScheibenbogenC.Quantification and characterization of specific T-cells by antigen-specific cytokine production using ELISPOT assay or intracellular cytokine staining.Methods2003; 31: 143–149.
72.
BettsM.R., AmbrozakD.R., DouekD.C.Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection.J Virol2001; 75: 11983–11991.
73.
RammenseeH.G., FalkK., RotzschkeO.Peptides naturally presented by MHC class I molecules.Annu Rev Immunol1993; 11: 213–244.
74.
FalkK., RotzschkeO., StevanovicS., JungG., RammenseeH.G.Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules.Nature1991; 351: 290–296.
75.
GuoH.C., JardetzkyT.S., GarrettT.P., LaneW.S., StromingerJ.L., WileyD.C.Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle.Nature1992; 360: 364–366.
76.
KuboR.T., SetteA., GreyH.M.Definition of specific peptide motifs for four major HLA-A alleles.J Immunol1994; 152: 3913–3924.
77.
HillA.V., ElvinJ., WillisA.C.Molecular analysis of the association of HLA-B53 and resistance to severe malaria.Nature1992; 360: 434–439.
78.
JardetzkyT.S., LaneW.S., RobinsonR.A., MaddenD.R., WileyD.C.Identification of self peptides bound to purified HLA-B27.Nature1991; 353: 326–329.
79.
FalkK., RotzschkeO., TakiguchiM.Peptide motifs of HLA-A1, -A11, -A31, and -A33 molecules.Immunogenetics1994; 40: 238–241.
80.
KikuchiA., SakaguchiT., MiwaK.Binding of nonamer peptides to three HLA-B51 molecules which differ by a single amino acid substitution in the A-pocket.Immunogenetics1996; 43: 268–276.
81.
SuttonJ., Rowland-JonesS., RosenbergW.A sequence pattern for peptides presented to cytotoxic T lymphocytes by HLA B8 revealed by analysis of epitopes and eluted peptides.Eur J Immunol1993; 23: 447–453.
82.
CaoT., DesombereI., VanlandschootP., SallbergM., Leroux-RoelsG.Characterization of HLA DR13-restricted CD4(+) T cell epitopes of hepatitis B core antigen associated with self-limited, acute hepatitis B.J Gen Virol2002; 83: 3023–3033.
83.
DesombereI., GijbelsY., VerwulgenA., Leroux-RoelsG.Characterization of the T cell recognition of hepatitis B surface antigen (HBsAg) by good and poor responders to hepatitis B vaccines.Clin Exp Immunol2000; 122: 390–399.
84.
PajotA., MichelM.L., Mancini-BourgineM.Identification of novel HLA-DR1-restricted epitopes from the hepatitis B virus envelope protein in mice expressing HLA-DR1 and vaccinated human subjects.Microbes Infect2006; 8: 2783–2790.
85.
DohH., RohS., LeeK.W., KimK.Response of primed human PBMC to synthetic peptides derived from hepatitis B virus envelope proteins: a search for promiscuous epitopes.FEMS Immunol Med Microbiol2003; 35: 77–85.
86.
HonoratiM.C., DolzaniP., MarianiE.Epitope specificity of Th0/Th2 CD4+ T-lymphocyte clones induced by vaccination with rHBsAg vaccine.Gastroenterology1997; 112: 2017–2027.
87.
DeulofeutH., IglesiasA., MikaelN.Cellular recognition and HLA restriction of a midsequence HBsAg peptide in hepatitis B vaccinated individuals.Mol Immunol1993; 30: 941–948.
88.
MinW.P., KamikawajiN., MinetaM., TanaT., KashiwagiS., SasazukiT.Identification of an epitope for T-cells correlated with antibody response to hepatitis B surface antigen in vaccinated humans.Hum Immunol1996; 46: 93–99.
89.
BlumH.E., LiangT.J., GalunE., WandsJ.R.Persistence of hepatitis B viral DNA after serological recovery from hepatitis B virus infection.Hepatology1991; 14: 56–63.
90.
HasegawaK., HuangJ., RogersS.A., BlumH.E., LiangT.J.Enhanced replication of a hepatitis B virus mutant associated with an epidemic of fulminant hepatitis.J Virol1994; 68: 1651–1659.
91.
BertolettiA., ChisariF.V., PennaA.Definition of a minimal optimal cytotoxic T-cell epitope within the hepatitis B virus nucleocapsid protein.J Virol1993; 67: 2376–2380.
92.
LeeH.G., LimJ.S., LeeK.Y.Peptide-specific CTL induction in HBV-seropositive PBMC by stimulation with peptides in vitro: novel epitopes identified from chronic carriers.Virus Res1997; 50: 185–194.
93.
TsaiS.L., ChenM.H., YehC.T.Purification and characterization of a naturally processed hepatitis B virus peptide recognized by CD8+ cytotoxic T lymphocytes.J Clin Invest1996; 97: 577–584.
94.
AndreF.Hepatitis B epidemiology in Asia, the Middle East and Africa.Vaccine2000; 18Suppl 1: S20–S22.
95.
CharronD. (Editor). HLA Genetic Diversity of HLA Function and Medical Implication, vol 1. EDK Medical and Scientific International Publisher1997; pp. 259–465.
96.
LaceyS.F., VillacresM.C., La RosaC.Relative dominance of HLA-B*07 restricted CD8+ T-lymphocyte immune responses to human cytomegalovirus pp65 in persons sharing HLA-A*02 and HLA-B*07 alleles.Hum Immunol2003; 64: 440–452.
97.
KiepielaP., LeslieA.J., HoneyborneI.Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA.Nature2004; 432: 769–775.
98.
GaudieriS., RauchA., ParkL.P.Evidence of viral adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection.J Virol2006; 80: 11094–11104.
99.
Neumann-HaefelinC., McKiernanS., WardS.Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution.Hepatology2006; 43: 563–572.
100.
BertolettiA., SouthwoodS., ChesnutR.Molecular features of the hepatitis B virus nucleocapsid T-cell epitope 18–27: interaction with HLA and T-cell receptor.Hepatology1997; 26: 1027–1034.
101.
ThimmeR., ChangK.M., PembertonJ., SetteA., ChisariF.V.Degenerate immunogenicity of an HLA-A2-restricted hepatitis B virus nucleocapsid cytotoxic T-lymphocyte epitope that is also presented by HLA-B51.J Virol2001; 75: 3984–3987.
102.
RehermannB., PasquinelliC., MosierS.M., ChisariF V.. Hepatitis B virus (HBV) sequence variation of cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection.J Clin Invest1995; 96: 1527–1534.
103.
JinY., ShihW.K., BerkowerI.Human T cell response to the surface antigen of hepatitis B virus (HBsAg). Endosomal and nonendosomal processing pathways are accessible to both endogenous and exogenous antigen.J Exp Med1988; 168: 293–306.
104.
FerrariC., CavalliA., PennaA.Fine specificity of the human T-cell response to the hepatitis B virus preS1 antigen.Gastroenterology1992; 103: 255–263.
105.
CelisE., OuD., OtvosL.Jr.. Recognition of hepatitis B surface antigen by human T lymphocytes. Proliferative and cytotoxic responses to a major antigenic determinant defined by synthetic peptides.J Immunol1988; 140: 1808–1815.
106.
BarnabaV., FrancoA., ParoliM.Selective expansion of cytotoxic T lymphocytes with a CD4+CD56+ surface phenotype and a T helper type 1 profile of cytokine secretion in the liver of patients chronically infected with Hepatitis B virus.J Immunol1994; 152: 3074–3087.
107.
BertolettiA., GehringA.J.The immune response during hepatitis B virus infection.J Gen Virol2006; 87: 1439–1449.
108.
WeimarW., HeijtinkR.A., ten KateF.J.Double-blind study of leucocyte interferon administration in chronic HBsAg-positive hepatitis.Lancet1980; 1: 336–338.
109.
FarrelP.J.S.G., DuboisM.F., RatnerL., SlatteryE.Interferon action: two distinct pathways for inhibition of protein synthesis by double-stranded RNA.Proc Acad Natl Sci U S A1987; 78: 5893–5897.
110.
GuntherS., PaulijW., MeiselH., WillH.Analysis of hepatitis B virus populations in an interferon-alpha-treated patient reveals predominant mutations in the C-gene and changing e-antigenicity.Virology1998; 244: 146–160.
111.
FlinkH.J., SprengersD., HansenB.E.Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon α-2b therapy.Gut2005; 54: 1604–1609.
112.
LohrH.F., WeberW., SchlaakJ., GoergenB., Meyer zum BuschenfeldeK.H., GerkenG.Proliferative response of CD4+ T cells and hepatitis B virus clearance in chronic hepatitis with or without hepatitis B e-minus hepatitis B virus mutants.Hepatology1995; 22: 61–68.
113.
MarinosG., TorreF., ChokshiS.Induction of T-helper cell response to hepatitis B core antigen in chronic hepatitis B: a major factor in activation of the host immune response to the hepatitis B virus.Hepatology1995; 22: 1040–1049.
114.
RossolS., MarinosG., CarucciP., SingerM.V., WilliamsR., NaoumovN.V.Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B.J Clin Invest1997; 99: 3025–3033.
115.
ZhangX., HanY., LuZ., GaoJ., LuoZ., ZhangD.Effect of multiple mutations in the core promoter and pre-core/core region of hepatitis B virus genome on the response to interferon in e antigen-positive chronic hepatitis B.J Gastroenterol Hepatol2001; 16: 393–398.
116.
RadeckeK., ProtzerU., TripplerM., Meyer Zum BuschenfeldeK.H., GerkenG.Selection of hepatitis B virus variants with aminoacid substitutions inside the core antigen during interferon-alpha therapy.J Med Virol2000; 62: 479–486.
117.
WielandS.F., GuidottiL.G., ChisariF.V.Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice.J Virol2000; 74: 4165–4173.
118.
CouxO., TanakaK., GoldbergA.L.Structure and functions of the 20S and 26S proteasomes.Annu Rev Biochem1996; 65: 801–847.
119.
GaczynskaM., RockK.L., GoldbergA.L.Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes.Nature1993; 365: 264–267.
120.
BoniC., PennaA., OggG.S.Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy.Hepatology2001; 33: 963–971.
121.
BoniC., PennaA., BertolettiA.Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B.J Hepatol2003; 39: 595–605.
122.
LaiC.L., ChienR.N., LeungN.W.A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.N Engl J Med1998; 339: 61–68.
123.
LiawY.F., LeungN.W., ChangT.T.Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.Gastroenterology2000; 119: 172–180.
124.
LeungN.W., LaiC.L., ChangT.T.Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy.Hepatology2001; 33: 1527–1532.
125.
ChangT.T., LaiC.L., ChienR.N.Four years of lamivudine treatment in Chinese patients with chronic hepatitis B.J Gastroenterol Hepatol2004; 19: 1276–1282.
126.
OcamaP., OpioC.K., LeeW.M.Hepatitis B virus infection: current status.Am J Med2005; 118: 1413.
127.
LauG.K., CooksleyH., RibeiroR.M.Impact of early viral kinetics on T-cell reactivity during antiviral therapy in chronic hepatitis.Antivir Ther2007; 12: 705–718.
128.
ChanH.L., TangJ.L., TamW., SungJ.J.The efficacy of thymosin in the treatment of chronic hepatitis B virus infection: a meta-analysis.Aliment Pharmacol Ther2001; 15: 1899–1905.
129.
ZavagliaC., SeveriniR., TinelliC.A randomized, controlled study of thymosin-alpha1 therapy in patients with anti-HBe, HBV-DNA-positive chronic hepatitis B.Dig Dis Sci2000; 45: 690–696.
130.
MutchnickM.G., LindsayK.L., SchiffE.R.Thymosin alpha1 treatment of chronic hepatitis B: results of a phase III multicentre, randomized, double-blind and placebo-controlled study.J Viral Hepat1999; 6: 397–403.
131.
MutchnickM.G., AppelmanH.D., ChungH.T.Thymosin treatment of chronic hepatitis B: a placebo-controlled pilot trial.Hepatology1991; 14: 409–415.
132.
ChienR.N., LiawY.F., ChenT.C., YehC.T., SheenI.S.Efficacy of thymosin alpha1 in patients with chronic hepatitis B: a randomized, controlled trial.Hepatology1998; 27: 1383–1387.
133.
ChowW.C., NgK.Y., McscnasS., LawN.M., NgH.S.The interim results of thymosin alpha 1 in a randomized controlled study in the treatment of chronic hepatitis B patients: Singapore experience.Hepatology1998; 28: 586A.
134.
MutchnickM., JaurequiJ., ShafritzD.Sustained response to thymosin therapy in patients with chronic hepatitis B.Hepatology1992; 16: 66A.
135.
HahmK.B., HanK.Y., KimW.H.Efficacy of polyadenylic.polyuridylic acid in the treatment of chronic active hepatitis B.Int J Immunopharmacol1994; 16: 217–225.
136.
CarrenoV., ZeuzemS., HopfU.A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B.J Hepatol2000; 32: 317–324.
137.
RigopoulouE.I., SuriD., ChokshiS.Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity.Hepatology2005; 42: 1028–1036.
MartinJ., BoschO., MoraledaG., BartolomeJ., QuirogaJ.A., CarrenoV.Pilot study of recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of chronic hepatitis B.Hepatology1993; 18: 775–780.
140.
PolS., NalpasB., DrissF.Efficacy and limitations of a specific immunotherapy in chronic hepatitis B.J Hepatol2001; 34: 917–921.
141.
HeathcoteJ., McHutchisonJ., LeeS.A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. The CY1899 T Cell Vaccine Study.
142.
RollierC., SunyachC., BarraudL.Protective and therapeutic effect of DNA-based immunization against hepadnavirus large envelope protein.Gastroenterology1999; 116: 658–665.
143.
PancholiP., LeeD.H., LiuQ.DNA prime/canarypox boost-based immunotherapy of chronic hepatitis B virus infection in a chimpanzee.Hepatology2001; 33: 448–454.
144.
Mancini-BourgineM., FontaineH., Scott-AlgaraD., PolS., BrechotC., MichelM.L.Induction or expansion of T-cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriers.Hepatology2004; 40: 874–882.
145.
YangS.H., LeeC.G., ParkS.H.Correlation of antiviral T-cell responses with suppression of viral rebound in chronic hepatitis B carriers: a proof-of-concept study.Gene Ther2006; 13: 1110–1117.
ChungM.K., YoonH., MinS.S.Induction of cytotoxic T lymphocytes with peptides in vitro: identification of candidate T-cell epitopes in hepatitis B virus X antigen.J Immunother1999; 22: 279–287.
148.
SchreuderG.M., HurleyC.K., MarshS.G.HLA dictionary 2004: summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens.Hum Immunol2005; 66: 170–210.
149.
MishraA., RaoK.V., DurgapalH., ManivelV., PandaS.K.Human T-helper cell responses to a synthetic peptide derived from the hepatitis B surface antigen.Immunology1993; 79: 362–367.
150.
MalmassariS.L., DengQ., FontaineH.Impact of hepatitis B virus basic core promoter mutations on T cell response to an immunodominant HBx-derived epitope.Hepatology2007; 45: 1199–1209.
