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

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00197.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. G162-G173 ◽

Cited By ~ 3

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.

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

Journal of Virology ◽

10.1128/jvi.00867-09 ◽

2009 ◽

Vol 83 (19) ◽

pp. 9652-9662 ◽

Cited By ~ 167

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.

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Analysis of the T cell response to the pre-S region of hepatitis B virus (HBV) in hepatitis B vaccine recipients

Journal of Hepatology ◽

10.1016/s0168-8278(88)80310-6 ◽

1988 ◽

Vol 7 ◽

pp. S128

Keyword(s):

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Cell Response ◽

T Cell Response ◽

Hepatitis B Vaccine ◽

B Virus

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Interleukin 21 augments the hepatitis B virus-specific CD8+ T-cell response in vitro in patients coinfected with HIV-1

AIDS ◽

10.1097/qad.0b013e328359b7ae ◽

2012 ◽

Vol 26 (17) ◽

pp. 2145-2153 ◽

Cited By ~ 8

Author(s):

Guangxu Ren ◽

Stefan Esser ◽

Christoph Jochum ◽

Joerg F. Schlaak ◽

Guido Gerken ◽

...

Keyword(s):

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

B Virus ◽

Interleukin 21 ◽

Hiv 1

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

Journal of Virology ◽

10.1128/jvi.76.17.8609-8620.2002 ◽

2002 ◽

Vol 76 (17) ◽

pp. 8609-8620 ◽

Cited By ~ 96

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.

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Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope.

Journal of Experimental Medicine ◽

10.1084/jem.180.3.933 ◽

1994 ◽

Vol 180 (3) ◽

pp. 933-943 ◽

Cited By ~ 156

Author(s):

A Bertoletti ◽

A Costanzo ◽

F V Chisari ◽

M Levrero ◽

M Artini ◽

...

Keyword(s):

Hepatitis B ◽

T Lymphocyte ◽

Negative Selection ◽

Cytotoxic T Lymphocyte ◽

Viral Persistence ◽

Hbv Infection ◽

Ctl Response ◽

B Virus ◽

Chronic Hbv ◽

Selection Of

Mutations that abrogate recognition of a viral epitope by class I-restricted cytotoxic T lymphocyte (CTL) can lead to viral escape if the CTL response against that epitope is crucial for viral clearance. The likelihood of this type of event is low when the CTL response is simultaneously directed against multiple viral epitopes, as has been recently reported for patients with acute self-limited hepatitis B virus (HBV) infection. The CTL response to HBV is usually quite weak, however, during chronic HBV infection, and it is generally acknowledged that this is a major determinant of viral persistence in this disease. If such individuals were to produce a mono- or oligospecific CTL response, however, negative selection of the corresponding mutant viruses might occur. We have recently studied two HLA-A2-positive patients with chronic hepatitis B who, atypically, developed a strong HLA-A2-restricted CTL response against an epitope (FLPSDFFPSV) that contains an HLA-A2-binding motif located between residues 18-27 of the viral nucleocapsid protein, hepatitis B core antigen (HBcAg). These patients failed, however, to respond to any of other HLA-A2-restricted HBV-derived peptides that are generally immunogenic in acutely infected patients who successfully clear the virus. Interestingly, DNA sequence analysis of HBV isolates from these two patients demonstrated alternative residues at position 27 (V --> A and V --> I) and position 21 (S --> N, S --> A, and S --> V) that reduced the HLA and T cell receptor-binding capacities of the variant sequences, respectively. Synthetic peptides containing these alternative sequences were poorly immunogenic compared to the prototype HBc18-27 sequence, and they could not be recognized by CTL clones specific for the prototype peptide. While we do not know if the two patients were originally infected by these variant viruses or if the variants emerged subsequent to infection because of immune selection, the results are most consistent with the latter hypothesis. If this is correct, the data suggest that negative selection of mutant viral genomes might contribute to viral persistence in a subset of patients with chronic HBV infection who express a narrow repertoire of anti-HBV CTL responses.

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