Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B

Stoop, Jeroen N.; Molen, Renate G. van der; Kuipers, Ernst J.; Kusters, Johannes G.; Janssen, Harry L.A.

doi:10.1016/j.virol.2006.11.018

Cited by 92 publications

(85 citation statements)

References 27 publications

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“…In this study, the results demonstrated a negative correlation between HBV-DNA levels and HBV-specific CTL responses in untreated CHB patients. These findings are in agreement with previous studies (14,17) and strengthen the evidence for an independent effect of viral load on the cellular immune response. …”

Section: Discussionsupporting

confidence: 93%

“…The results demonstrate a positive correlation between the magnitude of the HBV-specific T-cell responses and the duration of the HBV DNA suppression. The independent effect of the length of HBV DNA suppression on specific immune response, found in this study, was partly in accordance with previous studies (16,17). It is widely hypothesized that the T-cell function exhaustion of CHB patients occurs because of the prolonged exposure of T cells to high quantities of viral antigens and that T-cell resting from antigenic stimulation is a crucial requirement for restoration of a functional antiviral T-cell response (3,5,9,18).…”

Section: Discussionsupporting

confidence: 92%

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Effects of antiviral therapy on the cellular immune response in patients with chronic hepatitis B

Luo

Xia

Huang

et al. 2014

Molecular Medicine Reports

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Abstract.A weak T-cell immune response to the hepatitis B virus (HBV) is hypothesized to be the primary cause of chronic HBV infection. Emerging evidence suggests that long-term effective antiviral therapy restores the HBV-specific T-cell response from exhaustion. However, the extent to which the cellular immune response can be restored following the persistent suppression of HBV replication by antiviral therapy remains unclear. In order to investigate this question, 46 patients with chronic hepatitis B (CHB) treated with nucleos(t) ide analogues who demonstrated persistent suppression of HBV replication [defined as undetectable HBV DNA, hepatitis B e antigen (HBeAg) negative and adherence to antiviral therapy], 22 untreated CHB patients, 15 patients with acute hepatitis B (AHB) and 10 healthy adults were recruited. HBV-specific interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT) assay and HBV-specific T-cell proliferation analysis were performed with a panel of overlapping peptides covering the envelope and core antigens. Data from this study showed that the HBV-specific immune responses to the peptide pools of the envelope and core protein in the treated patients were stronger than those in the untreated CHB patients, but significantly weaker than those in the AHB patients and healthy adults. A higher frequency of response to S than C peptide pools was confirmed by the IFN-γ ELISPOT assay in the treated CHB patients. The restoration of antiviral immunity was clearly associated with a reduction in HBV DNA and the duration of HBV DNA suppression. In conclusion, the HBV-specific immune responses in the CHB patients can be significantly restored from exhaustion following the persistent suppression of HBV replication as a result of antiviral treatment with nucleos(t)ide analogues.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Effects of antiviral therapy on the cellular immune response in patients with chronic hepatitis B

Luo

Xia

Huang

et al. 2014

Molecular Medicine Reports

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“…Moreover, inhibition of viral replication reduces Treg counts and enhances the antiviral immune response in chronic hepatitis B patients (38). Tregs may also limit liver injury by controlling inflammation.…”

Section: Cd25mentioning

confidence: 99%

Adeno-Associated Virus-Mediated Gene Transfer Leads to Persistent Hepatitis B Virus Replication in Mice Expressing HLA-A2 and HLA-DR1 Molecules

Dion

Bourgine

Godon

et al. 2013

J Virol

104

125

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H epatitis B virus (HBV) infection is a major health problem.There are more than 350 million chronic carriers worldwide, and they are at high risk of developing liver cirrhosis and hepatocellular carcinoma (1). Chronic HBV infection is the result of impaired HBV-specific immune responses such that the infected hepatocytes cannot be eliminated or cured efficiently, but many of the associated issues remain unclear (2, 3).Due to the paucity of in vitro and in vivo models for HBV infection, HBV-transgenic mice are the most widely used model. These mice have the viral genome integrated into the chromosome and produce infectious HBV particles or viral antigens in the liver; however, the main limitation of HBV-transgenic mouse models is that they are immunologically tolerant to viral antigens (4, 5). Various routes have been exploited to introduce the HBV genome into the hepatocytes of adult mice. One is to introduce a replication-competent HBV genome into the mouse liver by hydrodynamic injection (HDI) through the tail vein (6); although HBV replicates in the mouse liver, the virus is rapidly cleared by immune responses against HBV proteins (7). Recently, Huang and colleagues used HDI to create a nontransgenic model of persistent HBV replication (8). The virus persisted in 40% of mice or was eliminated according to the genetic background. These mice rapidly develop anti-hepatitis B virus core (HBc) antibody, which is the first serological marker of acute HBV infection in humans. An alternative method uses adenoviral vectors to transfer 1.3 copies of the HBV genome into immunocompetent mice (9, 10), and acute or chronic HBV infection was obtained depending on the dose of adenoviral vector injected.Here, we describe an alternative murine model for the study of HBV persistence based on the liver-targeted transduction of adeno-associated virus serotype 2/8 (AAV2/8). We produced an AAV2/8 construct carrying a replication-competent HBV DNA genome and by intravenous injection established a model of HBV persistence in humanized HLA-A2/DR1 immunocompetent mice. Hepatitis B virus surface antigen (HBsAg), hepatitis B virus e antigen (HBeAg), and HBV DNA persisted for at least 1 year in sera of all AAV2/8-injected mice, and viral replication intermediates and transcripts were detected in their livers. HBcAg was expressed in 60% of hepatocytes without significant inflammation in the liver. The persistence of infection was associated with the presence of regulatory T cells (Tregs) in the liver. This mouse model of HBV persistence recapitulates viral and histological characteristics of human chronic HBV infection in the immunetolerant stage of the disease (11,12).In HLA-A2/DR1 mice, cellular immune responses were completely restricted to HLA molecules. Antibody, T-helper, and cytotoxic-T-lymphocyte responses to vaccination with recombinant HBsAg or HBsAg-expressing DNA were similar to those in vaccinated humans (13,14) or in HBV-infected individuals (15). Therefore, this AAV2/8-HBV-transduced HLA-A2/DR1 murine model may be useful fo...

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“…It has been reported that elevated numbers of Tregs can inhibit HBV-specific immune responses in a dose-dependent manner. 8 Depletion of Tregs has been shown to increase IFN-c production by HBV Ag-stimulated peripheral blood mononuclear cells. 20 Therefore, it is likely that the HBV-mediated enhancement in Tregs may, at least in part, contribute to immune tolerance and persistent infection in CHB patients.…”

Section: Enhancing Immune Response By Etv and Advmentioning

confidence: 99%

“…4 Recent findings suggest that regulatory T cells (Tregs) may also play a role in regulating immune responses to HBV infection. 8 High levels of Tregs have been detected in CHB and are thought to be responsible for the chronicity of hepatitis B infection, probably by inhibiting HBV-specific T-cell responses. However, Treg function also may be beneficial, limiting immune-mediated liver damage.…”

Section: Introductionmentioning

confidence: 99%

Enhancing the antihepatitis B virus immune response by adefovir dipivoxil and entecavir therapies

Jiang

et al. 2010

Cell Mol Immunol

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Chronicity of hepatitis B (CHB) infection is characterized by a weak immune response to the virus. Entecavir (ETV) and adefovir dipivoxil (ADV) are effective in suppressing hepatitis B virus (HBV) replication. However, the underlying immune mechanism in the antiviral response of patients treated with nucleoside or nucleotide analogs is not clearly understood. In this study, regulatory T cells (Tregs) and intracellular cytokines, including IL-2, interferon (IFN)-c, tumor-necrosis factor (TNF)-a and IL-4, were measured prior to and at 12, 24, 36 and 48 weeks after treatment with ETV or ADV. The cytokines were increased from 24 to 48 weeks after treatment. Higher levels of Th1 cytokines were observed with ETV (n529) versus ADV (n528) treatment. By contrast, the numbers of Tregs in both groups were decreased. The altered cytokine profile and cellular component was accompanied by a decrease in HBV DNA levels in both groups, which may contribute to their therapeutic effect in CHB infection. Our findings suggest that the antiviral effect of the drugs may be attributed not only to their direct effect on virus suppression but also to their immunoregulatory capabilities.

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Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B

Cited by 92 publications

References 27 publications

Effects of antiviral therapy on the cellular immune response in patients with chronic hepatitis B

Effects of antiviral therapy on the cellular immune response in patients with chronic hepatitis B

Adeno-Associated Virus-Mediated Gene Transfer Leads to Persistent Hepatitis B Virus Replication in Mice Expressing HLA-A2 and HLA-DR1 Molecules

Enhancing the antihepatitis B virus immune response by adefovir dipivoxil and entecavir therapies

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