Various findings concerning the clinical significance of quantitative changes in hepatitis B surface antigen (HBsAg) during the acute and chronic phase of hepatitis B virus (HBV) infection have been reported. In addition to being a biomarker of HBV-replication activity, it has been reported that HBsAg could contribute to the immunopathogenesis of HBV persistent infection. Moreover, HBsAg could become an attractive target for immune therapy, since the cellular and humeral immune response against HBsAg might be able to control the HBV replication and life cycle. However, several reports have described the immune suppressive function of HBsAg. HBsAg might suppress monocytes, dendritic cells (DCs), natural killer (NK), and natural killer T (NK-T) cells by direct interaction. On the other hand, cytotoxic T lymphocytes (CTLs) and helper T (Th) cells were exhausted by high amounts of HBsAg. In this paper, we focused on the immunological aspects of HBsAg, since better understanding of the interaction between HBsAg and immune cells could contribute to the development of an immune therapy as well as a biomarker of the state of HBV persistent infection.

https://downloads.hindawi.com/archive/2013/935295.pdf

Hepatitis B surface antigen could contribute to the immunopathogenesis of hepatitis B virus infection.

Hepatitis B virus (HBV) infection has persisted as a major public health problem due to the lack of an effective treatment for those chronically infected Therapeutic vaccination holds promise, and targeting HBV polymerase is pivotal for viral eradication In this research, a computational approach was employed to predict suitable HBV polymerase targeting multi-peptides for vaccine candidate selection We then performed in-depth computational analysis to evaluate the predicted epitopes’ immunogenicity, conservation, population coverage, and toxicity Lastly, molecular docking and MHC-peptide complex stabilization assay were utilized to determine the binding energy and affinity of epitopes to the HLA-A0201 molecule Criteria-based analysis provided four predicted epitopes, RVTGGVFLV, VSIPWTHKV, YMDDVVLGA and HLYSHPIIL Assay results indicated the lowest binding energy and high affinity to the HLA-A0201 molecule for epitopes VSIPWTHKV and YMDDVVLGA and epitopes RVTGGVFLV and VSIPWTHKV, respectively Regions 307 to 320 and 377 to 387 were considered to have the highest probability to be involved in B cell epitopes The T cell and B cell epitopes identified in this study are promising targets for an epitope-focused, peptide-based HBV vaccine, and provide insight into HBV-induced immune response

In Silico Analysis of Epitope-Based Vaccine Candidates against Hepatitis B Virus Polymerase Protein.

Hepatitis B virus (HBV) infection is a major cause of hepatic inflammation. Successful HBV clearance in patients is associated with sustained viral control by effector T cells. Compared with acute hepatitis B, chronic HBV infection is associated with the depletion of T cells, resulting in weak or absent virus‑specific T cells reactivity, which is described as 'exhaustion'. This exhaustion is characterized by impaired cytokine production and sustained expression of multiple coinhibitory molecules. Cytotoxic T lymphocyte‑associated antigen‑4 (CTLA‑4) is one of many coinhibitory molecules that can attenuate T cell activation by inhibiting costimulation and transmitting inhibitory signals to T cells. Persistent HBV infection results in the upregulation of CTLA‑4 on hepatic CD8+ T cells. This prompts CD8+ T cell apoptosis, and the activation of cytotoxic T lymphocytes is blocked. Similar to CD8+ T cells, CD4+ T helper (Th) cell proliferation is hindered following CTLA‑4 upregulation. In addition, the differentiation of CD4+ Th is polarized toward the Th2/peripherally‑inducible T regulatory cell types, increasing the levels of anti‑inflammatory cytokines. Conversely, the activation of proinflammatory cells (Th1 and follicular helper T) is blocked, and the levels of proinflammatory cytokines decline. This review summarizes the current literature relevant to T cell exhaustion in patients with HBV‑related chronic hepatitis, and discusses the roles of CTLA‑4 in T cell exhaustion.

/pdf/ctla-4-interferes-with-the-hbv-specific-t-cell-immune-17ur7luzrf.pdf

CTLA‑4 interferes with the HBV‑specific T cell immune response (Review).

Proper targeting of DNA vaccines has been identified as a crucial factor in improving the efficacy of DNA vaccines. In general, targeting measures affect either directly the DNA or the protein(s) expressed by DNA vaccines towards antigen-presenting cells (APC) to enable efficacious antigen presentation via MHC class I and II pathways. Improved targeting of the delivery of antigen can significantly increase the protective effects and reduce vaccination doses and toxicity. In this review, we summarize the targeting approaches reported in the scientific literature to improve DNA vaccine efficacy.

Approaches to improved targeting of DNA vaccines

Background/Aims: Signal transducer and activator of transcription (STAT) pathway plays an important role in antiviral efficacy of interferon alpha (IFN-α). IFN-α

Inhibition of STAT Pathway Impairs Anti-Hepatitis C Virus Effect of Interferon Alpha

Vaccination with a fusion DNA vaccine encoding hepatitis B surface antigen fused to the extracellular domain of CTLA4 enhances HBV-specific immune responses in mice: implication of its potential use as a therapeutic vaccine.

Objective: Seroclearance of hepatitis B surface antigen (HBsAg) remains a challenge to the functional cure of HBV infection due to an HBV-specific immune tolerance that prevents virus eradication. Methods: In this clinical study, chronic hepatitis B patients treated with the standard nucleotide analog (NA) Adefovir Dipivoxil (ADV) or treated with ADV and IFN- were immunized with granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with Human HBV Vaccine. Results: This THRIL-GM-Vac approach (THRee Injections of Low-dose GM-CSF followed by one dose of the HBV Vaccine) has achieved at least a 10-fold reduction of HBsAg level in 10 out of 23 (43.5%) patients tested. Moreover, two out of the 10 patients eventually reached seroclearance. Thus THRIL-GM-Vac could break HBV-specific tolerance and boost HBsAg-specific cellular immunity. Consequently, the THRIL-GM-Vac approach could provide an effective therapy for patients bearing medium-to-low levels of HBsAg. Conclusion: Our findings carry the clinical significance of showing a novel way to break immunotolerance that can tackle the persistent infection manifested as chronic HBV burden in chronic hepatitis B (CHB) patients.

Seroclearance of HBsAg in Chronic Hepatitis B Patients after a Tolerance Breaking Therapy: GM-CSF, followed by Human HBV Vaccine

Background: CD40 is an important costimulatory molecule in both celluar and humoral immune responses, involved in the pathogenic processes of chronic inflammatory diseases. Few studies were performed on the association of CD40 single nucleotide polymorphism (SNP) with chronic hepatitis B virus (HBV) infection. In this study, we studied whether the CD40-1C/T polymorphism had any effect on the progression of chronic HBV infection in Chinese population. Methods: CD40 -1C/T polymorphism in the 5′-untranslated region was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 453 chronic HBV carriers, who were divided into asymptomatic HBV carriers (ASC), moderate chronic hepatitis B group (MCHB) and severe chronic hepatitis B group (SCHB). 202 healthy individuals in the same region were enrolled in this study as the controls. The CD40 expression on B lymphocytes was detected by flow cytometry. The concentrations of soluble CD40 (sCD40) in sera were assayed by a commercial ELISA kit. Results: Our results showed the frequencies of TT genotype and T allele of CD40-1C/T polymorphism were higher significantly in ASC than those in controls (PPPConclusions: The CD40 -1C/T polymorphism may contribute to the susceptibility of asymptomatic HBV carriers through its effect on cell-surface CD40 expression, which indicated CD40 signaling was involved in immune tolerance of chronic HBV infection.

/pdf/association-of-cd40-1c-t-polymorphism-in-the-5-untranslated-1h3ips9zm2.pdf

Association of CD40 -1C/T polymorphism in the 5'-untranslated region with chronic HBV infection.

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Vaccination with a fusion DNA vaccine encoding hepatitis B surface antigen fused to the extracellular domain of CTLA4 enhances HBV-specific immune responses in mice: implication of its potential use as a therapeutic vaccine.

Seroclearance of HBsAg in Chronic Hepatitis B Patients after a Tolerance Breaking Therapy: GM-CSF, followed by Human HBV Vaccine

Association of CD40 -1C/T polymorphism in the 5'-untranslated region with chronic HBV infection.