Plasmids Enriched with CpG Motifs Activate Human Peripheral Blood Mononuclear Cells<i>In Vitro</i>and Enhance Th-1 Immune Responses to Hepatitis B Surface Antigen in Mice

Chen, Zhihui; Cao, Jie; Liao, Xiaoling; Ke, Jinshan; Zhu, Shanfeng; Zhao, Ping; Qi, Zhongtian

doi:10.1089/vim.2010.0116

Cited by 7 publications

(5 citation statements)

References 53 publications

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“…These may elicit undesirable outcomes in an in vivo application [23]. Relative to mammalian genomic DNA, the occurrence of CpG dinucleotides in prokaryote-derived pDNA is overrepresented [24] and reportedly binds a member of the Toll-like family of receptors, eliciting a T cell-mediated immune response [25], [26], [27]. In addition, reducing the amounts of detrimental impurities, including bacterial genomic DNA and endotoxins, is critical for production of plasmids used in vivo .…”

Section: Discussionmentioning

confidence: 99%

Production and Characterization of Novel Recombinant Adeno-Associated Virus Replicative-Form Genomes: A Eukaryotic Source of DNA for Gene Transfer

Dimitriadis

Yang

et al. 2013

PLoS ONE

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Conventional non-viral gene transfer uses bacterial plasmid DNA containing antibiotic resistance genes, cis-acting bacterial sequence elements, and prokaryotic methylation patterns that may adversely affect transgene expression and vector stability in vivo. Here, we describe novel replicative forms of a eukaryotic vector DNA that consist solely of an expression cassette flanked by adeno-associated virus (AAV) inverted terminal repeats. Extensive structural analyses revealed that this AAV-derived vector DNA consists of linear, duplex molecules with covalently closed ends (termed closed-ended, linear duplex, or “CELiD”, DNA). CELiD vectors, produced in Sf9 insect cells, require AAV rep gene expression for amplification. Amounts of CELiD DNA produced from insect cell lines stably transfected with an ITR-flanked transgene exceeded 60 mg per 5×109 Sf9 cells, and 1–15 mg from a comparable number of parental Sf9 cells in which the transgene was introduced via recombinant baculovirus infection. In mice, systemically delivered CELiD DNA resulted in long-term, stable transgene expression in the liver. CELiD vectors represent a novel eukaryotic alternative to bacterial plasmid DNA.

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Section: Discussionmentioning

confidence: 99%

Production and Characterization of Novel Recombinant Adeno-Associated Virus Replicative-Form Genomes: A Eukaryotic Source of DNA for Gene Transfer

Dimitriadis

Yang

et al. 2013

PLoS ONE

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“…These findings suggested a markedly increased number of IFN-γ-secreting CD8 + T cells, as well as CTL activity, in the Adv-HBcAg-TPPII group. Reports have suggested that T helper-1 (Th-1)-type immune responses are associated with viral clearance during infection with hepatitis B virus (HBV) [50], which may be important for HBV treatment. As shown above, Adv-HBcAg and Adv-HBcAg-TPPII significantly induced IL-2 and IFN-γ secretion, which indicated that Adv-HBcAg-TPPII triggers the Th1 immune response.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus Vector Harboring the HBcAg and Tripeptidyl Peptidase II Genes Induces Potent Cellular Immune Responses In Vivo

Tan¹,

Ma²,

Hu³

et al. 2017

Cell Physiol Biochem

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Background: Chronic hepatitis B virus (HBV) infection is associated with a weak but specific cellular immune response of the host to HBV. Tripeptidyl peptidaseⅡ (TPPⅡ), an intracellular macromolecule and proteolytic enzyme, plays an important complementary and compensatory role for the proteasome during viral protein degradation and major histocompatibility complex class I antigen presentation by inducing a specific cellular immune response in vivo. Based on a previous study, we aimed to explore the role of MHC class I antigen presentation in vivo and the mechanisms that may be involved. Methods: In this study, recombinant adenoviral vectors harboring the hepatitis B core antigen (HBcAg) and the TPPII gene were constructed (Adv-HBcAg and Adv-HBcAg-TPPII), and H-2Kd HBV-transgenic BALB/c mice and HLA-A2 C57BL/6 mice were immunized with these vectors, respectively. We evaluated the specific immune responses induced by Adv-HBcAg-TPPII in the HBV transgenic BALB/c mice and HLA-A2 C57BL/6 mice as well as the anti-viral ability of HBV transgenic mice, and we explored the underlying mechanisms. Results: We found that immunization with Adv-HBcAg-TPPII induced the secretion of the cytokines interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) as well as the activities of IFN-γ-secreting CD8+ T cells and CD4+ T cells. In addition, HBcAg-specific CTL activity in C57/BL mice and HBV transgenic animals was significantly enhanced in the Adv-HBcAg-TPPII group. Furthermore, Adv-HBcAg-TPPII decreased the hepatitis B surface antigen (HBsAg) and HBV DNA levels and the amount of HBsAg and HBcAg in liver tissues. Moreover, Adv-HBcAg-TPPII enhanced the expression of T-box transcription factor (T-bet) and downregulated GATA-binding protein 3 (GATA-3) while increasing the expression levels of JAK2, STAT1, STAT4 and Tyk2. Conclusions: These results suggested that the JAK/STAT signaling pathway participates in the CTL response that is mediated by the adenoviral vector encoding TPPII. Adv-HBcAg-TPPII could therefore break immune tolerance and stimulate HBV-specific cytotoxic T lymphocyte activity and could have a good therapeutic effect in transgenic mice.

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“…Previous studies have shown that CpG ODN treatments can enhance rHBsAg vaccine-induced immune responses and suppress HBV replication. [28][29][30] However, the goal of eradicating HBV without side effects has not yet been achieved. 31 Our data indicate that NP(HBV-CpG)-based therapy effectively aids in HBV clearance (Supporting Fig.…”

Section: Discussionmentioning

confidence: 99%

“…). Previous studies have shown that CpG ODN treatments can enhance rHBsAg vaccine‐induced immune responses and suppress HBV replication . However, the goal of eradicating HBV without side effects has not yet been achieved .…”

Section: Discussionmentioning

confidence: 99%

Nanoparticles encapsulating hepatitis B virus cytosine-phosphate-guanosine induce therapeutic immunity against HBV infection

Wang

Dou

et al. 2013

Hepatology

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Infection with hepatitis B virus (HBV) is the most common cause of liver disease worldwide. However, because the current interferon (IFN)-based treatments have toxic side effects and marginal efficacy, improved antivirals are essential. Here we report that unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) from the HBV genome (HBV-CpG) induced robust expression of IFN-a by plasmacytoid dendritic cells (pDCs) in a Toll-like receptor 9 (TLR9)-dependent manner. We also identified inhibitory guanosine-rich ODNs in the HBV genome (HBV-ODN) that are capable of inhibiting HBV-CpG-induced IFN-a production. Furthermore, nanoparticles containing HBV-CpG, termed NP(HBV-CpG), reversed the HBV-ODN-mediated suppression of IFN-a production and also exerted a strong immunostimulatory effect on lymphocytes. Our results suggest that NP(HBV-CpG) can enhance the immune response to hepatitis B surface antigen (HBsAg) and skew this response toward the Th1 pathway in mice immunized with rHBsAg and NP(HBV-CpG). Moreover, NP(HBV-CpG)-based therapy led to the efficient clearance of HBV and induced an anti-HBsAg response in HBV carrier mice. Conclusion: Endogenous HBV-CpG ODNs from the HBV genome induce IFN-a production so that nanoparticle-encapsulated HBV-CpG may act as an HBsAg vaccine adjuvant and may also represent a potent therapeutic agent for the treatment of chronic HBV infection. (HEPATOLOGY 2014;59:385-394) P ersistent infection with the hepatitis B virus (HBV) affects more than 360 million people worldwide and has become a severe public health problem owing to the increased risk of liver cirrhosis and hepatocellular carcinoma in infected individuals. The current recombinant hepatitis B surface antigen (rHBsAg) vaccine provides protection against HBV infection but fails to protect 10% of those who are vaccinated and is also ineffective for individuals who are already infected with HBV. Conventional antiviral drugs used for the treatment of HBV, including lamivudine and interferon-alpha (IFN-a), suppress viral replication and reduce hepatic symptoms. 1 However, the persistence of HBV covalently closed circular DNA (cccDNA) and defective immune responses lead to treatment failure and progression to liver disease. 2 Therefore, more efficient therapeutic strategies are needed to eradicate HBV infection.HBV seems to avoid inducing strong innate immune responses including the type I IFN response. 2 Therefore, methods of inducing vigorous immune responses against HBV may play a critical role in the clearance of HBV infection. The unmethylated cytosine-phosphate-guanosine (CpG) motifs presented in bacterial DNA can stimulate the immune system by interacting with the pattern-recognition receptor Tolllike receptor 9 (TLR9). 3 TLR9 is predominantly expressed in plasmacytoid dendritic cells (pDCs) and

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Plasmids Enriched with CpG Motifs Activate Human Peripheral Blood Mononuclear CellsIn Vitroand Enhance Th-1 Immune Responses to Hepatitis B Surface Antigen in Mice

Cited by 7 publications

References 53 publications

Production and Characterization of Novel Recombinant Adeno-Associated Virus Replicative-Form Genomes: A Eukaryotic Source of DNA for Gene Transfer

Production and Characterization of Novel Recombinant Adeno-Associated Virus Replicative-Form Genomes: A Eukaryotic Source of DNA for Gene Transfer

Adenovirus Vector Harboring the HBcAg and Tripeptidyl Peptidase II Genes Induces Potent Cellular Immune Responses In Vivo

Nanoparticles encapsulating hepatitis B virus cytosine-phosphate-guanosine induce therapeutic immunity against HBV infection

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