Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection

Zhao, Meng; Zhang, Xiaoyong; Pei, Rongjuan; Zhang, Ejuan; Kemper, Thekla; Vollmer, Jörg; Davis, Heather L.; Glebe, Dieter; Gerlich, Wolfram H.; Roggendorf, Michael; Lu, Mengji

doi:10.1016/j.antiviral.2015.11.001

Cited by 30 publications

(36 citation statements)

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“…CpG-ODN has a target site, namely pDCs, in mucosal vaccines (23), and it has been reported that CpG-ODN can increase the production of antibodies by 15 times as a vaccine adjuvant for hepatitis B vaccines (24). Consistently, the present study observed that the use of CpG-ODN as an adjuvant (B2 group) enhanced the levels of specific IgG antibody and cytokines, as well as the secretion of SIgA by the nasopharyngeal and vaginal mucosa.…”

Section: Discussionsupporting

confidence: 88%

Intramuscular primary immunization by nucleic acid vaccine pcDNA/Gpd‑IL‑2 and enhanced immunization with mucosal adjuvant CpG‑ODN and Gpd‑IL‑2 recombinant protein effectively induced strong mucosal immune responses and immune protective effects against Treponema pallidum skin infection

et al. 2018

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Abstract. The present study aimed to evaluate the immune effect of intramuscular primary immunization by the nucleic acid vaccine pcDNA/glycerophosphodiester phosphodiesterase-interleukin-2 (pcDNA/Gpd-IL-2) and enhanced immunization 2 weeks later with the combination of mucosal adjuvant CpG-oligodeoxynucleotides (ODN) and Gpd-IL-2 recombinant protein on skin infection caused by Treponema pallidum (Tp) in New Zealand rabbits. At week 8 following immunization, MTT assay was used to detect spleen cell proliferation, while enzyme-linked immunosorbent assay was performed to detect the cytokine and secretory immunoglobulin A (SIgA) levels. At week 10 after primary immunization, rabbits were inoculated with 10 5 Tp (Nichols strain). Alterations in the skin redness, swelling and ulceration were recorded for 0-60 days. In addition, positive rate of Tp in skin lesions and ulcer formation rate were examined using dark field and silver staining. The results indicated that intramuscular primary immunization by nucleic acid vaccine pcDNA/Gpd-IL-2 followed by enhanced immunization via nasal feeding with mucosal adjuvant CpG-ODN and Gpd-IL-2 recombinant protein induced the higher levels of Tp Gpd specific antibodies, increased the secretion of IL-2 and interferon-γ, and promoted the proliferation of T cells in the first 8 weeks after immunization. Furthermore, this immunization strategy stimulated the production of mucosa specific SIgA antibody. Thus, this strategy led to the lowest Tp positive and ulcer formation rates at the Tp infection sites, as well as healing of skin lesions on the earliest time point (day 42). In conclusion, immunization by nucleic acid vaccine pcDNA/Gpd-IL-2 followed by enhanced immunization with a combination of mucosal adjuvant CpG-ODN and Gpd-IL-2 recombinant protein is an effective immune strategy to induce strong mucosal immune responses and immune protective effects.

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Section: Discussionsupporting

confidence: 88%

Intramuscular primary immunization by nucleic acid vaccine pcDNA/Gpd‑IL‑2 and enhanced immunization with mucosal adjuvant CpG‑ODN and Gpd‑IL‑2 recombinant protein effectively induced strong mucosal immune responses and immune protective effects against Treponema pallidum skin infection

et al. 2018

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“…TLR9-L have also been tested in animal models of CHB infections. In HBV transgenic mice, hydrodynamically infected mice, and WHB-infected woodchucks, some anti-HBV activity has been described (20,22,40). However, the efficacy of such an approach These dilutions were used to stimulate 10 5 RPMI-B cells for 24 h before IL-6 ELISA measurement.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo stimulation of TLR9 is also an envisaged strategy in the fields of cancer and infectious disease therapies (15,16). TLR9 ligands (TLR9-L) are likely to be used in the HBV field as adjuvants for HBV vaccination (17)(18)(19) but have also been recently shown to induce an antiviral activity in animal models of HBV infection (20)(21)(22). However, regarding the latter, the antiviral effect obtained in the woodchuck model with a TLR9-L seems to be far less potent than that obtained with GS-9620 (14,22).…”

mentioning

confidence: 99%

“…TLR9 ligands (TLR9-L) are likely to be used in the HBV field as adjuvants for HBV vaccination (17)(18)(19) but have also been recently shown to induce an antiviral activity in animal models of HBV infection (20)(21)(22). However, regarding the latter, the antiviral effect obtained in the woodchuck model with a TLR9-L seems to be far less potent than that obtained with GS-9620 (14,22). Interestingly, it was recently demonstrated that TLR9-L were able to induce the formation of a myeloid cell-derived lymphoid structure in the liver of mice, called iMATEs, in which T lymphocytes can expand and mature to control chronic viral liver infections (23).…”

mentioning

confidence: 99%

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Interaction between Toll-Like Receptor 9-CpG Oligodeoxynucleotides and Hepatitis B Virus Virions Leads to Entry Inhibition in Hepatocytes and Reduction of Alpha Interferon Production by Plasmacytoid Dendritic Cells

Aillot

Bonnin

Ait-Goughoulte

et al. 2018

Antimicrob Agents Chemother

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We previously reported that Toll-like receptor 9 (TLR9)-CpG oligonucleotides could inhibit the establishment of hepatitis B virus (HBV) infections in hepatocytes. Our aim was to uncover the underlying mechanisms of this inhibition. HepaRG cells, RPMI-B lymphoblastoma cells, and primary plasmacytoid dendritic cells (pDCs) exposed to HBV and TLR9 ligands/agonists in various configurations were used. We observed an inhibition of HBV infection upon TLR9 stimulations only when agonist was applied during inoculation. This inhibition was independent of interleukin-6 (IL-6)/interferon-inducible protein 10 (IP-10) production as well as of TLR9 expression in hepatocytes. We further demonstrated an entry inhibition mechanism by showing a noncovalent binding of TLR9 agonist to HBV particles. Besides inhibiting HBV entry into hepatocytes, this biophysical interaction between HBV virions and TLR9 agonist was responsible for a reduction of alpha interferon (IFN-α) expression by pDCs. Interestingly, subviral particles composed of only HBsAg were able to genuinely inhibit the TLR9 pathway, without titrating TLR9 ligands. To conclude, our data suggest that synthetic TLR9-CpG oligonucleotides can strongly inhibit HBV entry by "coating" HBV virions and thereby preventing their interaction with cellular receptor. This titration effect of TLR9 agonist is also artifactually responsible for the inhibition of TLR9 engagement in pDCs, whereas a genuine inhibition of this innate pathway was confirmed with HBsAg subviral particles.

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“…However, TLR9 ligands have been successfully encapsulated into nanoparticles and have shown an improved efficacy in boosting prophylactic HBV immunization [113]. This could be helpful to improve the efficacy of TLR9 agonists in vivo, as TLR9 agonists have so far been shown to be less active as compared to those of TLR2 or TLR7 in the woodchuck model [114]. Other PRR agonists, including those working through cGAS and STING [115,116,117], or those working through RIG-I/NOD2 [118], are being investigated for their potential anti-HBV properties.…”

Section: Interplay Between Hbv and Innate Immunity: Therapeutic Inmentioning

confidence: 99%

Interplay between the Hepatitis B Virus and Innate Immunity: From an Understanding to the Development of Therapeutic Concepts

Faure-Dupuy

Lucifora

Durantel

2017

Viruses

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The hepatitis B virus (HBV) infects hepatocytes, which are the main cell type composing a human liver. However, the liver is enriched with immune cells, particularly innate cells (e.g., myeloid cells, natural killer and natural killer T-cells (NK/NKT), dendritic cells (DCs)), in resting condition. Hence, the study of the interaction between HBV and innate immune cells is instrumental to: (1) better understand the conditions of establishment and maintenance of HBV infections in this secondary lymphoid organ; (2) define the role of these innate immune cells in treatment failure and pathogenesis; and (3) design novel immune-therapeutic concepts based on the activation/restoration of innate cell functions and/or innate effectors. This review will summarize and discuss the current knowledge we have on this interplay between HBV and liver innate immunity.

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Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection

Cited by 30 publications

References 49 publications

Intramuscular primary immunization by nucleic acid vaccine pcDNA/Gpd‑IL‑2 and enhanced immunization with mucosal adjuvant CpG‑ODN and Gpd‑IL‑2 recombinant protein effectively induced strong mucosal immune responses and immune protective effects against Treponema pallidum skin infection

Intramuscular primary immunization by nucleic acid vaccine pcDNA/Gpd‑IL‑2 and enhanced immunization with mucosal adjuvant CpG‑ODN and Gpd‑IL‑2 recombinant protein effectively induced strong mucosal immune responses and immune protective effects against Treponema pallidum skin infection

Interaction between Toll-Like Receptor 9-CpG Oligodeoxynucleotides and Hepatitis B Virus Virions Leads to Entry Inhibition in Hepatocytes and Reduction of Alpha Interferon Production by Plasmacytoid Dendritic Cells

Interplay between the Hepatitis B Virus and Innate Immunity: From an Understanding to the Development of Therapeutic Concepts

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