T cell immunopathogenesis and immunotherapeutic strategies for chronic hepatitis B virus infection

Table 1 Immunotherapeutic approaches for animal models of hepatitis B virus infection

Animal model	Immunotherapy	Results	Ref.
Peptide vaccination
HBV transgenic mice	A synthesized fusion peptide, consisting HBcAg18-27 and HIV Tat49-57	Decrease in serum HBV DNA levels and the expression levels of HBsAg and HBcAg in the liver	[40]
Protein vaccination
HBV transgenic mice	HBsAg vaccine	Most of the mice showed reduction of HBV DNA levels and disappearance of HBeAg and HBsAg	[41]
Woodchuck hepatitis virus infection	Combination of vaccine of HBV large surface protein and clevudine	Restoration of T-cell response to Pre-S and S region	[42]
DNA immunization
Acute DHBV infection	DNA vaccine expressing DHBc and Pre-S/S and entecavir Boosted with fowl poxvirus vectors expressing DHBc and Pre-S/S	Clearance of DHBV infection at a rate of 100%	[43]
Chronic DHBV infection	DNA vaccine encoding the HBV large envelope and/or core protein with or without lamivudine	Reduction of viremia and liver DHBV cccDNA in 33% of ducks Seroconversion to anti-pre S in 67% of ducks showing cccDNA clearance	[44]
DC immunization
HBV transgenic mice	Activated bone marrow-derived DCs	Break CTL tolerance to HBsAg	[45]
HBV transgenic mice	Anti-CD40 agonistic monoclonal Ab	Induction of noncytopathic inhibition of HBV replication mediated by antiviral cytokines (IL-12 and TNF-α) produced by activated intrahepatic APCs	[46]
HBV transgenic mice	HBV-specific peptide-pulsed DCs	Reductions in the serum HBsAg and HBV DNA	[47]
Cytokines and adjuvants
HBV transgenic mice	Recombinant IL-12	Marked inhibition of HBV replication in the liver	[48]
HBV transgenic mice	α-galactosylceramide that can activate NK T cells	Complete inhibition of HBV replication	[49]
HBV transgenic mice	Recombinant IL-18	Inhibition of HBV replication noncytopathically, mediated by activation of resident intrahepatic NK cells and NK T cells	[50]
Gene therapy
HBsAg transgenic mice	Lentivectors expressing HBsAg and IgFc fusion Ag	Induction of seroconversion to anti-HBs	[51]

HBV: Hepatitis B virus; DHBV: Duck HBV; DC: Dendritic cell; HBsAg: Hepatitis B surface antigen; HBcAg: Hepatitis B core antigen; HIV: Human immunodeficiency virus; APC: Antigen-presenting cell; IL: Interleukin; NK: Natural killer; CTL: Cytotoxic T lymphocyte; TNF: Tumor necrosis factor; cccDNA: Covalently closed circular DNA; Ab: Antibody; Ag: Antigen.

Table 2 Immunotherapeutic trials for chronic hepatitis B virus infection in humans

Immunotherapy	Results	Ref.
Peptide vaccination
A vaccine with HBc18-27 peptide comprised of a T-helper cell epitope and two palmitic acid residues	Low levels of CTL activity were induced but no significant changes in liver biochemistry or viral serology were observed	[52]
Protein vaccination
PreS2/S (GenHevac B) or S (Recombivax)	HBe/anti-HBe seroconversion in 13% and HBV DNA negativity in 16% of the treated patients	[53]
Intradermal HBsAg vaccine and laimvudine in combination with IL-2	Induction of significant HBV DNA loss in the serum in two of five the treated patients	[54]
Oral administration of HBV envelope proteins (HBsAg + preS1 + preS2)	Induction of histological improvement in 30%, HBeAg negativity in 26.3% and HBsAg-specific T cell proliferation in 78% of the treated patients	[55]
IFN-α-2b monotherapy (9 mo) or IFN-α-2b plus pre-S2/S vaccine	Greater reduction in HBV DNA in patients with combination HBV therapy than those who received IFN-α-2b monotherapy	[56]
The combination with lamivudune and HBsAg vaccine in HBeAg+ cases	No improvement of HBe seroconversion rate in comparison with lamivudine therapy alone	[57]
Combination of lamivudine and HBsAg vaccine	Induction of sustained negativity of HBV DNA in 1/4 of patients	[58]
Combination of lamivudine and HBsAg vaccine	HBV DNA became undetectable in 64% of the patients, and was decreased in the remaining patients	[59]
DNA immunization
DNA vaccine encoding HBV envelope protein	Induction of an increase in HBV-specific IFN-γ-secreting T cells in nonresponders to conventional therapies, and HBV DNA levels were transiently decreased in 50% of vaccinated patients	[60]
DNA vaccine encoding PreS and S in patients with lamivudine breakthrough	Development of IFN-γ-producing T cells specific for preS or S antigen; Two of 10 patients showed seroconversion to anti-HBe	[61]
DC immunization
Peripheral blood-derived DCs, activated with GM-CSF and IL-4 pulsed with HBsAg	Both patients with normal and elevated ALT responded equally to DC vaccine and 53% of the patients showed induction of HBeAg negativity	[62]
Activated DCs from PBL with GM-CSF and IL-4, pulsed with two peptides, HBc18-27 and PreS2 44-53	Undetectable HBV DNA was achieved in 46.3% and 3.1% of HBeAg- and HBeAg+ patients, respectively. ALT normalization was observed in 69% and 30.5% of HBeAg- and HBeAg+ patients, respectively	[63]
Cytokines
GM-CSF	Safe and tolerable up to 1.0 μg/kg body weight, and induced HBV DNA negativity in 4/8 patients	[64]
Combination therapy with GM-CSF and HBsAg vaccine in HBV carrier children	Significant reduction of serum HBV DNA	[65]
High dose of IL-12 (0.5 μg/kg)	HBV DNA clearance was observed in 25% of the patients	[66]
Combination of IL-12 and lamivudine	Stimulation of T cell response to HBV with IFN-γ production. However, IL-12 was unable to suppress re-elevation of HBV DNA after cessation of lamivudine	[67]
Combination of IL-12 and IL-18	Stimulation of IFN-γ production by CD4+ T cells isolated from peripheral blood in response to HBcAg, and the effect was greater than those observed with either cytokine alone	[68]
α-galactosylceramide	Poorly tolerated and showed no clear suppressive effect on serum HBV DNA or ALT levels	[69]
Tα1
Combination of Tα1 and IFN-α	No statistically significant differences as compared with IFN-α monotherapy with respect to HBeAg seroconversion, changes in histology, normalization of ALT or loss of HBV DNA	[70]
Tα1 alone	At 12 mo after cessation of therapy, 36.4% of patients treated with 1.6 mg of Tα1 achieved ALT normalization, 15% achieved HBV DNA clearance by transcription-mediated amplification, and 22.8% achieved clearance of HBeAg	[71]
Comparative effect of Tα1 and IFN-α	Tα1 treatment was more effective in achieving ALT normalization and HBV DNA negativity at the end of the follow-up period than IFN-α	[72]
Combination of Tα1 and lamivudine	No any additional antiviral effect compared with lamivudine monotherapy as determined by HBe seroconversion and the emergence of viral breakthrough	[73]
Combination therapy with lamivudine and Tα1	Induction of significantly higher rates of ALT normalization, virological response, and HBeAg seroconversion than lamivudine monotherapy	[74]

HBV: Hepatitis B virus; Tα1: Thymosin α1; IFN: Interferon; ALT: Alanine aminotransferase; HBeAg: Hepatitis B e antigen; GM-CSF: Granulocyte-macrophage colony-stimulating factor; IL: Interleukin; CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; HBsAg: Hepatitis B surface antigen; HBcAg: Hepatitis B core antigen; PBL: Peripheral blood lymphocytes.