1. Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B: Perspectives and challenges 
Marie-Louise Michel, Qiang Deng, Maryline Mancini-Bourgine 
Journal of Hepatology 
Volume 54, Issue 6, Pages (June 2011)
DOI: /j.jhep
Copyright © 2011 European Association for the Study of the Liver Terms and Conditions

2. Fig. 1
Impairment of T-cell responses in chronic hepatitis B. T cells circulate in the liver through the sinusoidal network, in which they come into contact with hepatocytes and antigen-presenting cells (Kupffer cells and liver sinusoidal endothelial cells). During chronic hepatitis B virus infection, CD8 T cells in the liver encounter virus particles, viral antigens, and infected hepatocytes. They interact with infected hepatocytes and Kupffer cells through the T-cell receptor (TCR)-MHC class I-peptide complex. Hepatocytes over-expressing PD-L1 during chronic infection provide CD8 T cells with an inhibitory signal via the PD-1 pathway. This negative signal results in the impairment of T-cell functions: decreases in proliferation, cytotoxic function and in the production of anti-viral cytokines (IFN-γ and TNF-α). The presence of a large number of regulatory T cells (Tregs) and high levels of IL-10 secretion also contribute to T-cell exhaustion.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2011 European Association for the Study of the Liver Terms and Conditions

3. Fig. 2
General scheme of combined vaccination and antiviral drug treatment. In trials of combination treatment, patients suffering from chronic hepatitis B are enrolled and assigned to one of two groups (Groups A and B). Patients from both groups receive antiviral drugs. At the beginning of antiviral treatment or once HBV-DNA viral load has decreased to undetectable levels, multiple shots of the vaccine are administered to patients from group A. HBV DNA viral load, % HBeAg and HBsAg seroconversion are assessed. During antiviral treatment, viral and antigenic loads decrease and dysfunctional HBV-specific T cells are expected to recover. At the end of the clinical trial (after the last vaccine injection) treatment is stopped in both groups. ALT levels are continually monitored to ensure the rapid detection of liver damage. Viral rebound is expected in the patients of group B, whereas viremia control is expected in the patients of group A. In the patients of group A, HBV-specific and vaccine-activated T cells are expected to exert their antiviral functions, including the secretion of cytokines (IFN-γ, IL-2 and TNF-α) and proliferation.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2011 European Association for the Study of the Liver Terms and Conditions

4. Fig. 3
Gene therapy for chronic HBV infection. An immunotherapy protocol is established, combining vaccination and liver gene therapy. A recombinant HBV virus (rHBV) is designed, both as a gene delivery vector and as an antigen carrier, for intrahepatic expression of a foreign antigenic polyepitope. In this strategy, functional poly-epitope-specific T-cell responses will be generated in patients by vaccination before applying rHBV gene therapy. An rHBV is created in which the viral core gene is disrupted by the insertion of the foreign antigenic sequence. This core-deficient virus is not competent for replication unless the host hepatocyte provides the wild-type viral capsid protein in trans. The rHBV specifically infects human hepatocytes, as does the wild-type virus (wtHBV). However, rHBV cannot replicate in healthy recipients, and is maintained in chronically infected patients only in hepatocytes persistently infected with wtHBV. In the presence of HBV liver-specific promoters, rHBV proteins (polymerase, L, M, S envelopes, HBx) and the foreign antigenic polyepitope are produced, processed and presented as peptides on liver cells. The presentation of the foreign epitopes recruits vigorous functional T-cell response to the liver that should compensate for the dysfunctional HBV-specific T-cell response observed during persistent viral infection.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2011 European Association for the Study of the Liver Terms and Conditions

5. Journal of Hepatology 2011 54, 1286-1296DOI: (10. 1016/j. jhep. 2010
Copyright © 2011 European Association for the Study of the Liver Terms and Conditions