scholarly journals Rational Design of a Multiepitope Vaccine Encoding T-Lymphocyte Epitopes for Treatment of Chronic Hepatitis B Virus Infections

2007 ◽  
Vol 82 (1) ◽  
pp. 435-450 ◽  
Author(s):  
Erik Depla ◽  
Annegret Van der Aa ◽  
Brian D. Livingston ◽  
Claire Crimi ◽  
Koen Allosery ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Transgenic Mice ◽  
Immune Responses ◽  
T Lymphocyte ◽  
Plasmid Dna ◽  
Rational Design ◽  
Therapeutic Vaccine ◽  
Chronic Hepatitis B Virus ◽  
B Virus

ABSTRACT Protein sequences from multiple hepatitis B virus (HBV) isolates were analyzed for the presence of amino acid motifs characteristic of cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte (HTL) epitopes with the goal of identifying conserved epitopes suitable for use in a therapeutic vaccine. Specifically, sequences bearing HLA-A1, -A2, -A3, -A24, -B7, and -DR supertype binding motifs were identified, synthesized as peptides, and tested for binding to soluble HLA. The immunogenicity of peptides that bound with moderate to high affinity subsequently was assessed using HLA transgenic mice (CTL) and HLA cross-reacting H-2bxd (BALB/c × C57BL/6J) mice (HTL). Through this process, 30 CTL and 16 HTL epitopes were selected as a set that would be the most useful for vaccine design, based on epitope conservation among HBV sequences and HLA-based predicted population coverage in diverse ethnic groups. A plasmid DNA-based vaccine encoding the epitopes as a single gene product, with each epitope separated by spacer residues to enhance appropriate epitope processing, was designed. Immunogenicity testing in mice demonstrated the induction of multiple CTL and HTL responses. Furthermore, as a complementary approach, mass spectrometry allowed the identification of correctly processed and major histocompatibility complex-presented epitopes from human cells transfected with the DNA plasmid. A heterologous prime-boost immunization with the plasmid DNA and a recombinant MVA gave further enhancement of the immune responses. Thus, a multiepitope therapeutic vaccine candidate capable of stimulating those cellular immune responses thought to be essential for controlling and clearing HBV infection was successfully designed and evaluated in vitro and in HLA transgenic mice.

Multicistronic DNA-based therapeutic vaccine as a promising candidate to treat chronic hepatitis B virus (HBV) infection

2020 ◽  
Vol 73 ◽  
pp. S870-S871
Author(s):  
Helene Kerth ◽  
Anna Kosinska ◽  
Martin Kaechele ◽  
Andreas Oswald ◽  
Jinpeng Su ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Therapeutic Vaccine ◽  
Hbv Infection ◽  
Promising Candidate ◽  
Chronic Hepatitis B Virus ◽  
B Virus

scholarly journals Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus Infection

2011 ◽  
Vol 19 (2) ◽  
pp. 120-127 ◽  
Author(s):  
Jung Sun Yum ◽  
Byung Cheol Ahn ◽  
Hyun Jin Jo ◽  
Dong Yeon Kim ◽  
Ki Hyun Kim ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Transgenic Mice ◽  
Surface Antigen ◽  
Immune Therapy ◽  
Surface Antigens ◽  
Virus Surface ◽  
S Protein ◽  
Chronic Hepatitis B Virus ◽  
B Virus

ABSTRACTA hepatitis B virus (HBV) vaccine has been developed using a new adjuvant and HBV surface antigens produced from a CHO cell line. The purified HBV surface antigens are composed of L protein, M protein, and S protein in a mixture of 20- and 40-nm-diameter particles and filamentous forms. This HBV surface antigen, formulated with L-pampo, a proprietary adjuvant, induced 10 times more antibody than the same antigen with alum and was capable of inducing strong immune responses in three different HBV transgenic mice. In spite of the presence of a large amount of HBV antigen in the blood, no antibody against HBV surface antigen was normally detected in these transgenic mice. After immunization, the HBV antigen was also cleared from the blood.

New insight in the pathobiology of hepatitis B virus infection

Gut ◽  
2012 ◽  
Vol 61 (Suppl 1) ◽  
pp. i6-i17 ◽  
Author(s):  
Maura Dandri ◽  
Stephen Locarnini
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Immune Responses ◽  
Current Knowledge ◽  
Hbv Infection ◽  
Infected Hepatocyte ◽  
Hbv Replication ◽  
Chronic Hepatitis B Virus ◽  
B Virus ◽  
Important Host

Chronic hepatitis B virus (HBV) infection remains a major health burden and the main risk factor for the development of hepatocellular carcinoma worldwide. However, HBV is not directly cytopathic and liver injury appears to be mostly caused by repeated attempts of the host's immune responses to control the infection. Recent studies have shown that the unique replication strategy adopted by HBV enables it to survive within the infected hepatocyte while complex virus–host interplays ensure the virus is able to fulfil its replication requirements yet is still able to evade important host antiviral innate immune responses. Clearer understanding of the host and viral mechanisms affecting HBV replication and persistence is necessary to design more effective therapeutic strategies aimed at improving the management of patients with chronic HBV infection to eventually achieve viral eradication. This article focuses on summarising the current knowledge of factors influencing the course of HBV infection, giving emphasis on the use of novel assays and quantitative serological and intrahepatic biomarkers as tools for predicting treatment response and disease progression.

scholarly journals A Mechanism To Explain the Selection of the Hepatitis e Antigen-Negative Mutant during Chronic Hepatitis B Virus Infection

2008 ◽  
Vol 83 (3) ◽  
pp. 1379-1392 ◽  
Author(s):  
Lars Frelin ◽  
Therese Wahlström ◽  
Amy E. Tucker ◽  
Joyce Jones ◽  
Janice Hughes ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Liver Injury ◽  
Hepatitis B ◽  
Immune Responses ◽  
Hepatitis E ◽  
Core Antigen ◽  
Wild Type ◽  
Chronic Hepatitis B Virus ◽  
B Virus ◽  
Selection Of

ABSTRACT Hepatitis B virus (HBV) expresses two structural forms of the nucleoprotein, the intracellular nucleocapsid (hepatitis core antigen [HBcAg]) and the secreted nonparticulate form (hepatitis e antigen [HBeAg]). The aim of this study was to evaluate the ability of HBcAg- and HBeAg-specific genetic immunogens to induce HBc/HBeAg-specific CD4+/CD8+ T-cell immune responses and the potential to induce liver injury in HBV-transgenic (Tg) mice. Both the HBcAg- and HBeAg-specific plasmids primed comparable immune responses. Both CD4+ and CD8+ T cells were important for priming/effector functions of HBc/HBeAg-specific cytotoxic T-lymphocyte (CTL) responses. However, a unique two-step immunization protocol was necessary to elicit maximal CTL priming. Genetic vaccination did not prime CTLs in HBe- or HBc/HBeAg-dbl-Tg mice but elicited a weak CTL response in HBcAg-Tg mice. When HBc/HBeAg-specific CTLs were adoptively transferred into HBc-, HBe-, and HBc/HBeAg-dbl-Tg mice, the durations of the liver injury and inflammation were significantly greater in HBeAg-Tg recipient mice than in HBcAg-Tg mice. Importantly, liver injury in HBc/HBeAg-dbl-Tg mice was similar to the injury observed in HBeAg-Tg mice. Loss of HBeAg synthesis commonly occurs during chronic HBV infection; however, the mechanism of selection of HBeAg-negative variants is unknown. The finding that hepatocytes expressing wild-type HBV (containing both HBcAg and HBeAg) are more susceptible to CTL-mediated clearance than hepatocytes expressing only HBcAg suggest that the HBeAg-negative variant may have a selective advantage over wild-type HBV within the livers of patients with chronic infection during an immune response and may represent a CTL escape mutant.

scholarly journals The Influence of B and T Lymphocyte Attenuator Genetic Variants on Susceptibility to Chronic Hepatitis B Virus Infection

2018 ◽  
Vol 45 (6) ◽  
pp. 2540-2547 ◽  
Author(s):  
Jie Tang ◽  
Jiaqian Fei ◽  
Chunxia Gu ◽  
Weixia Liu ◽  
Minwei Li ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
T Lymphocyte ◽  
Genetic Variants ◽  
Chronic Hepatitis B Virus ◽  
B Virus ◽  
Chronic Hbv ◽  
Severe Chronic Hepatitis

Background/Aims: B and T lymphocyte attenuator (BTLA) is an immune inhibitory receptor involved in the pathogenesis of chronic viral infections. Little is known about the effects of BTLA gene polymorphisms on chronic hepatitis B virus (HBV) infections. In this study, we investigated whether the polymorphisms of BTLA are associated with the progression of chronic HBV infection. Methods: A total of 382 chronic HBV carriers and 170 healthy individuals in the same region were recruited for this study. The chronic HBV carriers were divided into three groups: asymptomatic HBV carriers (ASC), moderate chronic hepatitis B group (MCHB), and severe chronic hepatitis B group (SCHB). Two BTLA functional single nucleotide polymorphisms (SNPs; rs76844316 and rs9288952) were genotyped by polymerase chain reaction and sequenced directly. Results: The results showed that the frequency of the G allele of rs76844316 was significantly lower in the SCHB group than in the other three groups. Subjects bearing at least one G allele (TG or GG genotype) at rs76844316 had decreased susceptibility to severe chronic hepatitis B compared with those bearing the TT genotype. Haplotype analysis of the two SNPs revealed that the frequency of the G-G haplotype was significantly lower in SCHB patients than in controls. Moreover, in the SCHB group, patients carrying the G allele of rs76844316 tended to have lower ALT levels than those without it. Conclusion: Our findings suggest that the genetic variants of rs76844316 in BTLA influence the susceptibility to severe chronic hepatitis B and might play a protective role against the progression of chronic hepatitis B.

scholarly journals Hepatitis B Virus X Protein Increases 8-Oxo-7,8-Dihydro-2ʹ-Deoxyguanosine (8-Oxodg) Level via Repressing MTH1/ MTH2 Expression in Hepatocytes

2018 ◽  
Vol 51 (1) ◽  
pp. 80-96 ◽  
Author(s):  
Yan-Ting Lin ◽  
Wei Liu ◽  
Yun He ◽  
Yun-Li Wu ◽  
Wan-Nan Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Transgenic Mice ◽  
Hbv Infection ◽  
Luciferase Reporter ◽  
Sequencing Analysis ◽  
X Protein ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Background/Aims: Chronic hepatitis B virus (HBV) infection markedly increases the risk of development of hepatocellular carcinoma (HCC). Among the seven viral proteins that HBV encodes, HBV X protein (HBx) appears to have the most oncogenic potential. The mitochondria-associated HBx can induce oxidative stress in hepatocytes, leading to the production of abundant reactive oxygen species (ROS). High levels of ROS usually induce oxidative DNA damage and 8-hydroxy-2-deoxyguanosine (8-OHdG), also known as 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG), which is one of the major products of DNA oxidation and an important biomarker for oxidative stress and carcinogenesis. Cells have evolved a mechanism to prevent oxidized nucleotides from their incorporation into DNA through nucleotide pool sanitization enzymes of MTH1 (NUDT1), MTH2 (NUDT15), MTH3 (NUDT18) and NUDT5. However, little is known as to whether HBx can regulate the expression of those enzymes and modulate the formation and accumulation of 8-oxodG in hepatocytes. Methods: The level of 8-oxodG was assessed by ELISA in stable HBV-producing hepatoma cell lines, an HBV infectious mouse model, HBV and HBx transgenic mice and HBV-infected patients versus their respective controls. Expression of MTH1, MTH2, MTH3 and NUDT5 was determined by a real-time quantitative PCR and western blot analysis. Transcriptional regulation of MTH1 and MTH2 expression by HBx and the effect of HBx on MTH1 and MTH2 promoter hypermethylation were examined using a luciferase reporter assay and bisulfite sequencing analysis. Results: In comparison with controls, significantly higher levels of 8-oxodG were detected in the genome and culture supernatant of stable HBV-producing HepG2.2.15 cells, in the sera and liver tissues of HBV infectious mice and HBV or HBx transgenic mice, and in the sera of HBV-infected patients. Expression of HBx in hepatocytes significantly increased 8-oxodG level and reduced the expression of MTH1 and MTH2 at both mRNA and protein levels. It was also demonstrated that HBx markedly attenuated the MTH1 or MTH2 promoter activities through hypermethylation. Furthermore, enhancement of 8-oxodG production by HBx was reversible by overexpression of MTH1 and MTH2. Conclusion: Our data show that HBx expression results in the accumulation of 8-oxodG in hepatocytes through inhibiting the expression of MTH1 and MTH2. This may implicate that HBx may act as a tumor promoter through facilitating the mutational potential of 8-oxodG thus connecting a possible link between HBV infection and liver carcinogenesis.

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