Immune and Viral Profile from Tolerance to Hepatitis B Surface Antigen Clearance: a Longitudinal Study of Vertically Hepatitis B Virus-Infected Children on Combined Therapy

Carey, Ivana; D’Antiga, Lorenzo; Bansal, Sanjay; Longhi, Maria Serena; Ma, Yuanfang; Mesa, I. Rebollo; Mieli‐Vergani, Giorgina; Vergani, Diego

doi:10.1128/jvi.01449-10

Cited by 56 publications

(55 citation statements)

References 36 publications

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“…A proportion of the untreated patients exhibited HBV-specific CTL responses that were weak. These findings are consistent with the majority of previous studies (7,10,14). In the treated CHB patients, the frequency and magnitude of the antigen-specific T cell responses were significantly higher than those in the untreated CHB patient group.…”

Section: Discussionsupporting

confidence: 92%

“…To date, the majority of published studies (7,8,10,11) have focused on the immune profile of HBsAg-negative patients who are defined as having complete control of HBV infection. These studies indicate that a substantial restoration of the exhausted HBV-specific T-cell response results from long-term effective therapy.…”

Section: Effects Of Antiviral Therapy On the Cellular Immune Responsementioning

confidence: 99%

“…After isolation, the PBMCs were used for the in vitro experiment, and the rest were cryopreserved in 90% FBS and 10% dimethyl sulfoxide at -80˚C for future use. described (7,8). The antigens for the IFN-γ ELISPOT assays were the two pools of overlapping peptides (S-pool and C-pool).…”

Section: Separation Of Peripheral Blood Mononuclear Cells (Pbmcs)mentioning

confidence: 99%

“…The permanent suppression of HBV replication following treatment requires a robust acquired immune response against the HBV core and envelope antigens (5). There is evidence that antiviral therapy alters the balance between host immunity and viral replication, enabling weakened virus-specific immune responses to strengthen, broaden, and possibly control the infection, probably due to the decreased HBV antigen levels allowing the recovery of the T-cell response (6)(7)(8)(9). This mechanism may be important in contributing to complete recovery from CHB.…”

Section: Introductionmentioning

confidence: 99%

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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: 92%

Section: Effects Of Antiviral Therapy On the Cellular Immune Responsementioning

confidence: 99%

Section: Separation Of Peripheral Blood Mononuclear Cells (Pbmcs)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…[30][31][32] The second mechanism is by the induction of inferior specific immune responses including deficiency of HBV-specific CTLs and low levels of antiviral cytokine production. 29,33,34 For a successful immunotherapeutic approach, one should aim to break and overcome both of these immune tolerance mechanisms to mount an effective counterattack. We propose that our protocol of sustained stimulation via three daily pretreatments with GM-CSF before HBV vaccination induced significantly higher levels of DC maturation compared to pre-treatment for one or two days, enabling DCs to present antigen more effectively to the adaptive immune system.…”

Section: Discussionmentioning

confidence: 99%

Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice

Wang

Dong²,

Xiao

et al. 2015

Cell Mol Immunol

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to be a potential vaccine adjuvant despite contradictory results from animal and human studies. The discrepancies may be due to the different doses and regimens of GM-CSF that were used, given that either mature or immature dendritic cells (DCs) could be induced under different conditions. To test the hypothesis that GM-CSF can be used as a novel adjuvant for a hepatitis B virus (HBV) therapeutic vaccine, we administered GM-CSF once per day for three days prior to vaccination with recombinant HBV vaccine (rHBVvac) in mice. We observed greater DC maturation in these pre-treated animals at day 3 as compared to day 1 or day 2 of daily GM-CSF administration. This strategy was further investigated for its ability to break the immune tolerance established in hepatitis B surface antigen-transgenic (HBsAg-Tg) animals. We found that the levels of induced anti-HBsAg antibodies were significantly higher in animals following three days of GM-CSF pre-treatment before rHBV vaccination after the third immunization. In addition to the increase in anti-HBsAg antibody levels, cell-mediated anti-HBsAg responses, including delayed-type hypersensitivity, T-cell proliferation, interferon-c production, and cytotoxic T lymphocytes, were dramatically enhanced in the three-day GM-CSF pre-treated group. After adoptive transfers of CD8 1 T cells from immunized animals, antigen-specific CD8 1 T cells were observed in the livers of recipient HBsAg-Tg animals. Moreover, the three-day pre-treatments with GM-CSF prior to rHBVvac vaccination could significantly eliminate HBsAg-positive hepatocytes, suggesting beneficial therapeutic effects. Therefore, this protocol utilizing GM-CSF as an adjuvant in combination with the rHBVvac vaccine has the potential to become a novel immunotherapy for chronic hepatitis B patients. Cellular & Molecular Immunology

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Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections

2015

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause a large proportion of acute and chronic liver disease worldwide. Over the past decades many immunological studies defined host immune responses that mediate spontaneous clearance of acute HBV and HCV infection. However, host immune responses are also relevant in the context of treatment-induced clearance of chronic HBV and HCV infection. First, the pretreatment level of interferon-stimulated genes as well as genetic determinants of innate immune responses, such as single nucleotide polymorphisms near the IFNL3 gene, are strong predictors of the response to interferon-alpha (IFN-α)-based therapy. Second, IFN-α, which has been a mainstay of HBV and HCV therapy over decades, and ribavirin, which has also been included in interferon-free direct antiviral therapy for HCV, modulate host immune responses. Third, both IFN-α-based and IFN-α-free treatment regimens of HBV and HCV infection alter the short-term and long-term adaptive immune response against these viruses. Finally, treatment studies have not just improved the clinical outcomes, but also provided opportunities to study virus-host interaction. This review summarizes our current knowledge on how a patient's immune response affects the treatment outcome of HBV and HCV infection and how innate and adaptive immune responses themselves are altered by the different treatment regimens.

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Immune and Viral Profile from Tolerance to Hepatitis B Surface Antigen Clearance: a Longitudinal Study of Vertically Hepatitis B Virus-Infected Children on Combined Therapy

Cited by 56 publications

References 36 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

Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice

Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections

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