scholarly journals Modulation of the CD8+-T-Cell Response by CD4+ CD25+ Regulatory T Cells in Patients with Hepatitis B Virus Infection

2005 ◽  
Vol 79 (6) ◽  
pp. 3322-3328 ◽  
Author(s):  
Ornella Franzese ◽  
Patrick T. F. Kennedy ◽  
Adam J. Gehring ◽  
Jim Gotto ◽  
Roger Williams ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Regulatory T Cells ◽  
Ex Vivo ◽  
T Cell Response ◽  
Hbv Infection ◽  
Peripheral Tolerance ◽  
B Virus

ABSTRACT CD4+ CD25+ regulatory T cells have been shown to maintain peripheral tolerance against self and foreign antigens. In this study we analyzed the effect of circulating CD4+ CD25+ T cells on CD8+-T-cell responses of patients with chronic and resolved hepatitis B virus (HBV) infection. We demonstrated that circulating CD4+ CD25+ T cells modulate the function and expansion of HBV-specific CD8+ cells ex vivo in all patients, regardless of whether they have chronic or resolved HBV infection. The possible role of CD4+ CD25+ T cells in the pathogenesis of chronic HBV infection is not supported by these data. However, these results might have implications for optimizing future immunotherapeutic approaches to HBV treatment.

scholarly journals Hepatitis B virus-triggered PTEN/β-catenin/c-Myc signaling enhances PD-L1 expression to promote immune evasion

2020 ◽  
Vol 318 (1) ◽  
pp. G162-G173 ◽  
Author(s):  
Yishuang Sun ◽  
Mengxue Yu ◽  
Mengmeng Qu ◽  
Yuhong Ma ◽  
Dandan Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Immune Evasion ◽  
Cell Response ◽  
T Cell Response ◽  
Hbv Infection ◽  
B Virus

Hepatitis B virus (HBV) exploits multiple strategies to evade host immune surveillance. Programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling plays a critical role in regulating T cell homeostasis. However, it remains largely unknown as to how HBV infection elevates PD-L1 expression in hepatocytes. A mouse model of HBV infection was established by hydrodynamic injection with a vector containing 1.3-fold overlength HBV genome (pHBV1.3) via the tail vein. Coculture experiments with HBV-expressing hepatoma cells and Jurkat T cells were established in vitro. We observed significant decrease in the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and increase in β-catenin/PD-L1 expression in liver tissues from patients with chronic hepatitis B and mice subjected to pHBV1.3 hydrodynamic injection. Mechanistically, decrease in PTEN enhanced β-catenin/c-Myc signaling and PD-L1 expression in HBV-expressing hepatoma cells, which in turn augmented PD-1 expression, lowered IL-2 secretion, and induced T cell apoptosis. However, β-catenin disruption inhibited PTEN-mediated PD-L1 expression, which was accompanied by decreased PD-1 expression, and increased IL-2 production in T cells. Luciferase reporter assays revealed that c-Myc stimulated transcriptional activity of PD-L1. In addition, HBV X protein (HBx) and HBV polymerase (HBp) contributed to PTEN downregulation and β-catenin/PD-L1 upregulation. Strikingly, PTEN overexpression in hepatocytes inhibited β-catenin/PD-L1 signaling and promoted HBV clearance in vivo. Our findings suggest that HBV-triggered PTEN/β-catenin/c-Myc signaling via HBx and HBp enhances PD-L1 expression, leading to inhibition of T cell response, and promotes HBV immune evasion. NEW & NOTEWORTHY This study demonstrates that during HBV infection, HBV can increase PD-L1 expression via PTEN/β-catenin/c-Myc signaling pathway, which in turn inhibits T cell response and ultimately promotes HBV immune evasion. Targeting this signaling pathway is a potential strategy for immunotherapy of chronic hepatitis B.

scholarly journals Cytotoxic T-Lymphocyte Antigen 4 Gene and Recovery from Hepatitis B Virus Infection

2004 ◽  
Vol 78 (20) ◽  
pp. 11258-11262 ◽  
Author(s):  
Chloe L. Thio ◽  
Timothy L. Mosbruger ◽  
Richard A. Kaslow ◽  
Christopher L. Karp ◽  
Steffanie A. Strathdee ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
T Lymphocyte ◽  
Cell Response ◽  
Cytotoxic T Lymphocyte ◽  
Viral Persistence ◽  
T Cell Response ◽  
Hbv Infection ◽  
B Virus

ABSTRACT Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an inhibitory T-cell receptor expressed by activated and regulatory T cells. We hypothesized that single-nucleotide polymorphisms (SNPs) in the gene encoding CTLA-4 may affect the vigor of the T-cell response to hepatitis B virus (HBV) infection, thus influencing viral persistence. To test this hypothesis, we genotyped six CTLA4 SNPs, from which all frequent haplotypes can be determined, using a large, matched panel of subjects with known HBV outcomes. Haplotypes with these SNPs were constructed for each subject using PHASE software. The haplotype distribution differed between those with viral persistence and those with clearance. Two haplotypes were associated with clearance of HBV infection, which was most likely due to associations with the SNPs −1722C (odds ratio [OR] = 0.60, P = 0.06) and +49G (OR = 0.73, P = 0.02). The wild-type haplotype, which contains an SNP leading to a decreased T-cell response (+6230A), was associated with viral persistence (OR = 1.32, P = 0.04). These data suggest that CTLA4 influences recovery from HBV infection, which is consistent with the emerging role of T regulatory cells in the pathogenesis of disease.

scholarly journals Immunogenicity and Tolerogenicity of Hepatitis B Virus Structural and Nonstructural Proteins: Implications for Immunotherapy of Persistent Viral Infections

2002 ◽  
Vol 76 (17) ◽  
pp. 8609-8620 ◽  
Author(s):  
Kazuhiro Kakimi ◽  
Masanori Isogawa ◽  
JoSan Chung ◽  
Alessandro Sette ◽  
Francis V. Chisari
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Viral Infections ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Response ◽  
Hbv Infection ◽  
Peripheral Tolerance ◽  
Specific Ctls ◽  
B Virus

ABSTRACT Persistent hepatitis B virus (HBV) infection is characterized by a weak and narrowly focused CD8+ T-cell response to HBV that is thought to reflect the induction of central and/or peripheral tolerance to HBV proteins in neonatal and adult onset infections, respectively. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may lead to viral clearance in chronically infected individuals. The present study was performed to compare the relative immunogenicities and tolerogenicities of HBV structural (envelope [ENV]) and nonstructural (polymerase [POL]) proteins at the CD8+ cytotoxic T lymphocyte (CTL) level in transgenic mice that replicate HBV in the liver and secrete infectious virus into the blood, thus representing an excellent model of persistent HBV infection. Interestingly, the mice were tolerant to the ENV but not to the POL proteins at the CTL level. Furthermore, the POL-specific CTLs had no impact on HBV replication or liver function in vivo, even though they were readily induced and reached the liver after DNA immunization, reflecting their relatively low avidity and the low level at which the POL protein is expressed by the hepatocyte. Collectively, these results suggest that the factors that make POL less tolerogenic also make POL-specific CTLs relatively inefficient effector cells when they reach the target organ. Immunotherapeutic strategies to control HBV infection by inducing virus-specific CTL responses in chronically infected subjects should be evaluated in light of this observation.

scholarly journals Characterization of Hepatitis B Virus (HBV)-Specific T-Cell Dysfunction in Chronic HBV Infection

2007 ◽  
Vol 81 (8) ◽  
pp. 4215-4225 ◽  
Author(s):  
Carolina Boni ◽  
Paola Fisicaro ◽  
Caterina Valdatta ◽  
Barbara Amadei ◽  
Paola Di Vincenzo ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Hbv Infection ◽  
Chronic Hbv Infection ◽  
Cell Dysfunction ◽  
B Virus ◽  
T Cell Dysfunction ◽  
Chronic Hbv

ABSTRACT Dysfunctional CD8+ T cells present in chronic virus infections can express programmed death 1 (PD-1) molecules, and the inhibition of the engagement of PD-1 with its ligand (PD-L1) has been reported to enhance the antiviral function of these T cells. We took advantage of the wide fluctuations in levels of viremia which are typical of chronic hepatitis B virus (HBV) infection to comprehensively analyze the impact of prolonged exposure to different virus quantities on virus-specific T-cell dysfunction and on its reversibility through the blocking of the PD-1/PD-L1 pathway. We confirm that chronic HBV infection has a profound effect on the HBV-specific T-cell repertoire. Despite the use of a comprehensive panel of peptides covering all HBV proteins, HBV-specific T cells were rarely observed directly ex vivo in samples from patients with chronic infection, in contrast to those from patients with acute HBV infection. In chronic HBV infection, virus-specific T cells were detected mainly in patients with lower levels of viremia. These HBV-specific CD8+ T cells expressed PD-1, and their function was improved by the blocking of PD-1/PD-L1 engagement. Thus, a broad spectrum of anti-HBV immunity is expressed by patients with chronic HBV infection and this spectrum is proportional to HBV replication levels and can be improved by blocking the PD-1/PD-L1 pathway. This information may be useful for the design of immunotherapeutic strategies to complement and optimize available antiviral therapies.

scholarly journals CD8+ T Cells Mediate Viral Clearance and Disease Pathogenesis during Acute Hepatitis B Virus Infection

2003 ◽  
Vol 77 (1) ◽  
pp. 68-76 ◽  
Author(s):  
Robert Thimme ◽  
Stefan Wieland ◽  
Carola Steiger ◽  
John Ghrayeb ◽  
Keith A. Reimann ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Cell Subset ◽  
T Cell Response ◽  
Viral Clearance ◽  
Hbv Infection ◽  
Disease Pathogenesis ◽  
Effector Cells ◽  
B Virus

ABSTRACT Although the CD4+- and CD8+-T-cell responses to the hepatitis B virus (HBV) are thought to be crucial for the control of HBV infection, the relative contribution of each T-cell subset as an effector of viral clearance is not known. To examine this question, we monitored the course of HBV infection in control, CD4-depleted, and CD8-depleted chimpanzees. Our results demonstrate that CD8+ cells are the main effector cells responsible for viral clearance and disease pathogenesis during acute HBV infection, and they suggest that viral clearance is mediated by both noncytolytic and cytolytic effector functions of the CD8+-T-cell response.

How Far we are towards Eradication of HBV Infection

2015 ◽  
Vol 24 (4) ◽  
pp. 473-479 ◽  
Author(s):  
Mihai Voiculescu
Keyword(s):  
Immune Response ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
T Cell Receptors ◽  
Hepatitis B Surface Antigen ◽  
Hbv Infection ◽  
Major Health Problem ◽  
Cell Receptors ◽  
B Virus

Hepatitis B virus (HBV) infection is a major health problem with an important biological and a significant socio-economic impact all over the world. There is a high pressure to come up with a new and more efficient strategy against HBV infection, especially after the recent success of HCV treatment. Preventing HBV infection through vaccine is currently the most efficient way to decrease HBV-related cirrhosis and liver cancer incidence, as well as the best way to suppress the HBV reservoir. The vaccine is safe and efficient in 80-95% of cases. One of its most important roles is to reduce materno-fetal transmission, by giving the first dose of vaccine in the first 24 hours after birth. Transmission of HBV infection early in life is still frequent, especially in countries with high endemicity.Successful HBV clearance by the host is immune-mediated, with a complex combined innate and adaptive cellular and humoral immune response. Different factors, such as the quantity and the sequence of HBV epitope during processing by dendritic cells and presenting by different HLA molecules or the polymorphism of T cell receptors (TOL) are part of a complex network which influences the final response. A new potential therapeutic strategy is to restore T-cell antiviral function and to improve innate and adaptive immune response by immunotherapeutic manipulation.It appears that HBV eradication is far from being completed in the next decades, and a new strategy against HBV infection must be considered. Abbreviations: ALT: alanine aminotransferase; APC: antigen presenting cells; cccDNA: covalently closed circular DNA; HBIG: hepatitis B immunoglobulin; HbsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; CTL: cytotoxic T lymphocyte; IFN: interferon; NUC: nucleos(t)ide analogues; pg RNA: pre genomic RNA; TLR: toll-like receptors; TOL: T cell receptors.

272 Use of LioCyx-M, autologous hepatitis B virus (HBV)-Specific T cell receptor (TCR) T-cells, in advanced HBV-related hepatocellular carcinoma (HCC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A297-A297
Author(s):  
Fu-Sheng Wang ◽  
Fanping Meng ◽  
Jiehua Jin ◽  
Yuanyuan Li ◽  
Regina Wanju Wong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
T Cell Receptor ◽  
Dose Level ◽  
Cell Receptor ◽  
Hbv Dna ◽  
B Virus

BackgroundWe have demonstrated the ability of Hepatitis-B-virus (HBV)-specific T cell receptor (TCR) bioengineered T cells to recognize and lyse Hepatocellular carcinoma (HCC) cells expressing HBV antigens derived from HBV-DNA integration in patients with liver transplant.1 LioCyx-M is an immunotherapeutic product composing of autologous T cells transiently modified with in-vitro transcribed mRNA encoding HBV-specific TCR. The transient TCR expression makes LioCyx -M amenable to a dose escalating posology.MethodsThe primary endpoint of this phase 1 trial is to assess the safety and tolerability of LioCyx-M in patients with advanced HBV-HCC without curative treatment options. Eligible patients were diagnosed with Barcelona clinic liver cancer stage B or C HCC (Child-Pugh < 7 points), receiving >1 year antiviral treatment prior to enrollment. These patients had matching HLA class I genotypes which present HBV encoded antigen. Peripheral blood was collected from each patient prior to each dose for LioCyx-M manufacturing. Patients received 4 escalating doses of 1×104 cells/kg, 1×105 cells/kg, 1×106 cells/kg, 5×106 cells/kg bodyweight (BW) in the first treatment cycle, each intravenously administered weekly. Patients underwent 1-month safety assessment post the 4th infusion, according to Common Terminology NCI CTCAE Version 4.0.3. If there were no dose associated toxicities, patients were eligible to continue administration of LioCyx-M at dose of 5 × 106 cells/kg BW weekly. Tumor response per RECIST 1.1 criteria and survival time were assessed.ResultsAt data cutoff (30 April 2020), eight patients were enrolled, with a median age of 53 (range: 49 - 67). These patients received a median number of 6 (range: 4 - 12) infusions of LioCyx-M. 1 patient developed Grade 3 elevations in alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST) and bilirubin after receiving LioCyx-M at dose level of 1×105 cells/kg BW. Another patient had Grade 1 transient fever after receiving LioCyx-M at dose level 5×106 cells/kg BW in the 4th, 5th and 6th infusions. No treatment-related adverse events (trAEs) such as cytokine release syndrome or neurotoxicity were observed. No fatal trAEs were observed. The median time to progression was 1.9 months (range: 0.2 - 9.5 months). The median overall survival was 34 months (range: 3 - 38.2 months).ConclusionsThe encouraging clinical outcome and tolerable safety highlight the good benefit-risk profile of LioCyx-M. Therefore, further exploration of efficacy of LioCyx-M treatment for advanced HBV-HCC is warranted in a Phase 2 proof-of-concept clinical study.AcknowledgementsFunding: Lion TCR.Trial RegistrationNCT03899415Ethics ApprovalThe study was approved by Fifth Medical Center of Chinese PLA General Hospital’s Ethics Board, approval number R2016185DI010.ReferenceTan AT, Yang N, Lee Krishnamoorthy T, et al. Use of Expression Profiles of HBV-DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy. Gastroenterology 2019;156(6):1862–1876.e9.

scholarly journals The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection

2009 ◽  
Vol 83 (19) ◽  
pp. 9652-9662 ◽  
Author(s):  
Shinichi Asabe ◽  
Stefan F. Wieland ◽  
Pratip K. Chattopadhyay ◽  
Mario Roederer ◽  
Ronald E. Engle ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Cell Response ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Viral Spread ◽  
B Virus ◽  
T Cell Priming ◽  
Kinetics Of

ABSTRACT The impact of virus dose on the outcome of infection is poorly understood. In this study we show that, for hepatitis B virus (HBV), the size of the inoculum contributes to the kinetics of viral spread and immunological priming, which then determine the outcome of infection. Adult chimpanzees were infected with a serially diluted monoclonal HBV inoculum. Unexpectedly, despite vastly different viral kinetics, both high-dose inocula (1010 genome equivalents [GE] per animal) and low-dose inocula (10° GE per animal) primed the CD4 T-cell response after logarithmic spread was detectable, allowing infection of 100% of hepatocytes and requiring prolonged immunopathology before clearance occurred. In contrast, intermediate (107 and 104 GE) inocula primed the T-cell response before detectable logarithmic spread and were abruptly terminated with minimal immunopathology before 0.1% of hepatocytes were infected. Surprisingly, a dosage of 101 GE primed the T-cell response after all hepatocytes were infected and caused either prolonged or persistent infection with severe immunopathology. Finally, CD4 T-cell depletion before inoculation of a normally rapidly controlled inoculum precluded T-cell priming and caused persistent infection with minimal immunopathology. These results suggest that the relationship between the kinetics of viral spread and CD4 T-cell priming determines the outcome of HBV infection.

Hepatitis B virus-specific T cell receptors with high functional avidity redirect T cells to eliminate HBV

2017 ◽  
Vol 66 (1) ◽  
pp. S29-S30
Author(s):  
K. Wisskirchen ◽  
J. Kah ◽  
K. Metzger ◽  
L. Weigand ◽  
W. Uckert ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
T Cell Receptors ◽  
Functional Avidity ◽  
Cell Receptors ◽  
B Virus
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