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

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.

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

Journal of Virology ◽

10.1128/jvi.78.20.11258-11262.2004 ◽

2004 ◽

Vol 78 (20) ◽

pp. 11258-11262 ◽

Cited By ~ 84

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.

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

Journal of Virology ◽

10.1128/jvi.79.6.3322-3328.2005 ◽

2005 ◽

Vol 79 (6) ◽

pp. 3322-3328 ◽

Cited By ~ 173

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.

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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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How Far we are towards Eradication of HBV Infection

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld.2014.1121.244.hbv ◽

2015 ◽

Vol 24 (4) ◽

pp. 473-479 ◽

Cited By ~ 4

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.

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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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Naturally Occurring Hepatitis B Virus B-Cell and T-Cell Epitope Mutants in Hepatitis B Vaccinated Children

The Scientific World JOURNAL ◽

10.1155/2013/571875 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 15

Author(s):

Yu-Min Lin ◽

Guey-Mei Jow ◽

Shu-Chi Mu ◽

Bing-Fang Chen

Keyword(s):

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

B Cell ◽

Cell Epitope ◽

Hbv Infection ◽

Core Antigen ◽

T Cell Epitope ◽

Naturally Occurring ◽

B Virus

To control hepatitis B virus (HBV) infection, a universal HBV vaccination program for infants was launched in Taiwan in 1984. The aim of this study was to investigate the role of B-cell and T-cell epitope variations of HBsAg and polymerase in HBV infection in vaccinated children. One hundred sixty-three sera from vaccinated children were enrolled randomly. HBV serum markers, including hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) and core antigen (anti-HBc), were detected by ELISA. Nucleotide sequences encoding the S and the pre-S regions of HBsAg were analyzed in all HBsAg positive sera. Five children were HBsAg positive. Sequence analysis of S, pre-S, and overlapped polymerase (P) genes showed that HBV isolates of HBsAg-positive vaccinees were variants; no G145R but G145A and other substitutions were found in the “a” determinant. Fifteen, six, and eight amino acid substitutions within B-cell and T-cell epitopes of S, pre-S, and P regions were detected, respectively. Several immune-epitope mutants, such as S45T/A, N131T, I194V, and S207N in S, were detected in all isolates. In conclusion, our results suggested that these naturally occurring immunoepitope mutants, which changed their immunogenicity leading to escape from immune response, might cause HBV infection.

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