Restored Function of HBV-Specific T Cells After Long-term Effective Therapy With Nucleos(t)ide Analogues

Boni, Carolina; Laccabue, Diletta; Lampertico, Pietro; Giuberti, T.; Viganò, Mauro; Schivazappa, Simona; Alfieri, Arianna; Pesci, Marco; Gaeta, Giovanni Battista; Brancaccio, Giuseppina; Colombo, Massimo; Missale, Gabriele; Ferrari, Carlo

doi:10.1053/j.gastro.2012.07.014

Cited by 305 publications

(283 citation statements)

References 25 publications

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“…However, they were still significantly weaker than those in the AHB patients and healthy adults. These findings are consistent with the results from Boni et al (10), which showed that the T-cell responses in the NUC-treated patients with HBV DNA suppression but HBsAg persistence were markedly stronger than in the untreated patients with CHB, but were significantly weaker than in the patients with HBsAg clearance and anti-HBsAg antibody generation. As a result of the wide variability of responses among the treated groups, certain treated patients with persistent HBV-DNA negative status exhibited a less efficient immune response than those of particular untreated patients.…”

Section: Discussionsupporting

confidence: 92%

“…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%

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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: Discussionsupporting

confidence: 92%

Section: Effects Of Antiviral Therapy On the Cellular Immune Responsementioning

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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“…Furthermore, CD40 signaling can aid effective activation of T cells or prevent T cell exhaustion (Krug et al, 2001;Fonteneau et al, 2003;Tel et al, 2013;Fuse et al, 2009;Isogawa et al, 2013). In CHB patients low and exhausted T cells are consistently observed and held responsible for the inability to clear HBV (Ferrari et al, 1990;Jung et al, 1991;Boni et al, 2007Boni et al, , 2012Bertoletti and Ferrari, 2016). In CHB patients and individuals homozygous for rs179008 less induction of CD40 may thus affect the ability of pDCs to drive adaptive immune responses and could facilitate T cell exhaustion.…”

Section: Discussionmentioning

confidence: 99%

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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A B S T R A C TTLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance.Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054).Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.

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“…Firstly, HBV-specific T-cells are functionally impaired in CHB. It has been reported that NAs may indirectly promote a reduction of PD-1 level and restore HBV-specific T-cell responsiveness by efficiently suppressing HBV DNA replication, even though NA treatment has no remarkable effects on the survival and function of immune cells (25). Secondly, regulatory T-cells (Tregs) and dendritic cells (DCs) play key roles in immune response regulation.…”

Section: Discussionmentioning

confidence: 99%

HBsAg seroclearance or seroconversion induced by peg-interferon alpha and lamivudine or adefovir combination therapy in chronic hepatitis B treatment: a meta-analysis and systematic review

Zhang¹,

Chen²,

Chi³

et al. 2016

Rev Esp Enferm Dig

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Background and aims: Seroclearance or seroconversion of hepatitis B surface antigen (HBsAg) is generally considered as a clinical endpoint. The purpose of the present meta-analysis was to evaluate the effect of combined therapy with pegylated interferon alpha (PEG-IFNα) with or without lamivudine (LAM) or adefovir (ADV) on HBsAg seroclearance or seroconversion in subjects with chronic hepatitis B (CHB).Methods: Randomized controlled trials performed through May 30 th 2015 in adults with CHB receiving PEG-IFNα and LAM or ADV combination therapy or monotherapy for 48-52 weeks were included. The Review Manager Software 5.2.0 was used for the meta-analysis.Results: No statistical differences in HBsAg seroclearance (9.9% vs. 7.1%, OR = 1.47, 95% CI: 0.75, 2.90; p = 0.26) or HBsAg seroconversion (4.2% vs. 3.7%, OR = 1.17, 95% CI: 0.57, 2.37; p = 0.67) rates were noticed between PEG-IFNα + LAM and PEG-IFN α + placebo during post-treatment follow-up for 24-26-weeks in subjects with hepatitis Be antigen (HBeAg)-positive CHB.No statistical differences in HBsAg clearance (10.5% vs. 6.4%, OR = 1.68, 95% CI: 0.75, 3.76; p = 0.21) were seen, but statistical differences in HBsAg seroconversion (6.3% vs. 0%, OR = 7.22, 95% CI: 1.23, 42.40; p = 0.03) were observed, between PEG-IFNα + ADV and PEG-IFNα for 48-52 weeks of treatment in subjects with HBeAg-positive CHB.A systematic evaluation showed no differences in HBsAg disappearance and seroconversion rates between PEG-IFNα + placebo and PEG-IFNα + LAM for 48-52 weeks in subjects with HBeAg-positive CHB.A systematic assessment found no differences in HBsAg disappearance and seroconversion rates between PEG-IFNα + placebo and PEG-IFNα + LAM during 24 weeks' to 3 years' followup after treatment in subjects with HBeAg-negative CHB.Conclusion: Combined therapy with PEG-IFNα and LAM or ADV was not superior to monotherapy with PEG-IFNα in terms of HBsAg seroclearance or seroconversion

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Restored Function of HBV-Specific T Cells After Long-term Effective Therapy With Nucleos(t)ide Analogues

Cited by 305 publications

References 25 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

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

HBsAg seroclearance or seroconversion induced by peg-interferon alpha and lamivudine or adefovir combination therapy in chronic hepatitis B treatment: a meta-analysis and systematic review

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