Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B

Lebossé, Fanny; Testoni, Barbara; Fresquet, Judith; Facchetti, F.; Galmozzi, E.; Fournier, Morgane; Hervieu, Valérie; Berthillon, Pascale; Berby, Françoise; Bordes, Isabelle; Durantel, David; Levrero, Massimo; Lampertico, Pietro; Zoulim, Fabien

doi:10.1016/j.jhep.2016.12.024

Cited by 120 publications

(136 citation statements)

References 71 publications

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“…This control seems to be immune‐mediated as a result of reduction in HBsAg. It has been shown that large amounts of HBsAg have immunosuppressive effects in HBV infection and its clearance in the circulation establishes a more permissive immunological environment where functional control can be restored. Recent results indicate that REP 2139 exposure has no direct immunostimulatory properties .…”

Section: Discussionmentioning

confidence: 99%

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Mijočević

Karimzadeh

Seebach

et al. 2018

Journal of Viral Hepatitis

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Summary The treatment of patients suffering from HBeAg‐positive chronic hepatitis B with REP 2139‐Ca resulted in potent reductions in HBsAg and HBV DNA, seroconversion to anti‐HBs and the establishment of functional control of infection. In this cohort of 12 patients, we investigated whether differences between HBsAg sequences might explain the lack of response to REP 2139‐Ca observed in 3 of 12 patients. We also assessed if the reduction or complete loss of HBsAg in serum observed during therapy were caused by mutations in the “a” determinant preventing the detection of HBsAg by standard diagnostic assays. The complete pre‐S/S open reading frame (ORF) was sequenced and pre‐S1, pre‐S2 and S amino acid sequences were analysed. We found no major differences between pre‐S1, pre‐S2 and S sequences in responders and nonresponders correlated with low reduction in HBsAg. In addition, we found no mutations in the “a” determinant that would significantly affect the reactivity of HBsAg in diagnostic assays. These results demonstrate that the amino acid sequence of complete pre‐S/S ORF has no direct influence on response to REP 2139‐Ca therapy.

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Section: Discussionmentioning

confidence: 99%

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Mijočević

Karimzadeh

Seebach

et al. 2018

Journal of Viral Hepatitis

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“…Of note, HBeAg(−) CI patients had the highest percentage amongst all groups, suggesting that p38MAPK could contribute to inhibition of viral replication, though without affecting HBsAg expression. The lack of correlation between HBsAg and serum HBV‐DNA as well as intrahepatic cccDNA has been previously reported in HBeAg(−) CHB patients, indicating different mechanisms to control HBsAg production …”

Section: Discussionmentioning

confidence: 78%

p38 mitogen‐activated protein kinase impairment of innate immune cells is a characteristic feature of HBeAg‐negative chronic hepatitis B

Bakarozi

Mavropoulos

Bogdanos

et al. 2019

Journal of Viral Hepatitis

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The mitogen‐activated protein kinase p38 (MAPK) is implicated in the induction of immune responses by regulating the differentiation of T lymphocytes and production of cytokines. Our aim was to investigate p38MAPK phosphorylation in different stages of the natural history of hepatitis B virus (HBV) infection. Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll‐Hypaque density‐based centrifugation from 10 patients with HBeAg‐negative chronic hepatitis B [HBeAg(−) CHB;HBV‐DNA>2000IU/mL], eight patients with HBeAg‐negative chronic HBV infection [HBeAg(−) CI;undetectable HBV‐DNA] and 8 healthy controls (HCs). p38MAPK phosphorylation was assessed by phospho‐specific flow cytometry in PBMCs and cell subsets (CD3+,CD3−,CD56+,CD56−) after stimulation with cytokines (IL‐12+IL‐2 and IL‐12+IL‐18) or nonspecific stimuli [arsenite, phorbol 12‐myristate 13‐acetate (PMA) and ionomycin] at 0,30,60,120 and 240 minutes using p38 phospho‐specific conjugated antibodies. ΙFN‐γ was determined by ELISA in PBMCs culture supernatants after stimulation with rhIL‐2, rhIL‐12 and rhIL‐18, with and without pre‐treatment with the p38 MAPK inhibitor, SB203580. HBeAg(−) CI patients showed the highest expression of phosphor‐p38 MAPK in total PBMCs and subpopulations compared to HBeAg(−) CHB and HCs. A striking impairment in p38 phosphorylation was noted in CD56+ cells and in especially in NK cells (CD3‐CD56+). SB203580‐induced inhibition of p38MAPK phosphorylation was associated with suppression of IFN‐γ production in all groups. The universal lack of p38 MAPK activation in CD56+ and in particular in NK cells from HBeAg(−) CHB patients during viremia suggests a potential cell‐dependent implication of this pathway in the natural history of HBV infection.

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“…Through the establishment of a cccDNA minichromosome in infected hepatocytes, viral replication may initially occur without raising the attention of intrinsic antiviral defense mechanisms [22,23,24]. The cccDNA is the template of transcription for five viral RNAs necessary for the production of the viral antigens and for viral replication, the latter of which takes place in the cytoplasm after reverse transcription of an over-length pregenomic RNA (pgRNA) within newly formed nucleocapsids [25].…”

Section: Cccdna Activity and Pool Sizementioning

confidence: 99%

The Role of cccDNA in HBV Maintenance

Allweiss

Dandri

2017

Viruses

141

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Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide; it can cause various degrees of liver damage and is strongly associated with the development of liver cirrhosis and hepatocellular carcinoma. The molecular mechanisms determining HBV persistence are not fully understood, but these appear to be multifactorial and the unique replication strategy employed by HBV enables its maintenance in infected hepatocytes. Both the stability of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the hepatocyte nucleus, and the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity. Since a true cure of HBV requires clearance of intranuclear cccDNA from infected hepatocytes, understanding the mechanisms involved in cccDNA biogenesis, regulation and stability is mandatory to achieve HBV eradication. This review will summarize the state of knowledge on these mechanisms including the impact of current treatments on the cccDNA stability and activity. We will focus on events challenging cccDNA persistence in dividing hepatocytes.

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Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B

Cited by 120 publications

References 71 publications

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

p38 mitogen‐activated protein kinase impairment of innate immune cells is a characteristic feature of HBeAg‐negative chronic hepatitis B

The Role of cccDNA in HBV Maintenance

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