A Hepatitis B Virus-Derived Peptide Exerts an Anticancer Effect via TNF/iNOS-producing Dendritic Cells in Tumor-Bearing Mouse Model

Recently, we reported a 6-mer hepatitis B virus (HBV)-derived peptide, Poly6, that exerts antiviral effects against human immunodeficiency virus type 1 (HIV-1). Here, we explored the immunotherapeutic potential of Poly6 via its administration into dendritic cells (DCs) in a mouse model. Our data revealed that Poly6 treatment led to enhanced production of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS)-producing DCs (Tip-DCs) in a type 1 interferon (IFN-I)-dependent manner via the induction of mitochondrial stress. Poly6 treatment in mice implanted with MC38 cells, a murine colon adenocarcinoma line, led to attenuated tumor formation, primarily due to direct cell death induced by Tip-DC mediated nitric oxide (NO) production and indirect killing by Tip-DC mediated cluster of differentiation 8 (CD8) cytotoxic T lymphocyte (CTL) activation via CD40 activation. Moreover, Poly6 treatment demonstrated an enhanced anticancer effect with one of the checkpoint inhibitors, the anti PD-L1 antibody. In conclusion, our data reveal that Poly6 treatment elicits an antitumor immune response in mice, possibly through NO-mediated oncolytic activity via Tip-DC activation and Tip-DC mediated CTL activation. This suggests that Poly6 represents a potential adjuvant for cancer immunotherapy by enhancing the anticancer effects of immune checkpoint inhibitors.

Download Full-text

A Hepatitis B Virus-Derived Peptide Can Inhibit Infection of Human Lung Cells with SARS-CoV-2 in a Type-1 Interferon-Dependent Manner

Viruses ◽

10.3390/v13071227 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1227

Author(s):

Yu-Min Choi ◽

Hyein Jeong ◽

Uni Park ◽

Nam-Hyuk Cho ◽

Bum-Joon Kim

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Antiviral Effect ◽

Epithelial Cell Line ◽

Dependent Manner ◽

Type 1 Interferon ◽

Human Lung Cells ◽

B Virus ◽

Hiv 1

The current COVID-19 pandemic has highlighted the urgent need to develop effective therapeutic strategies. We evaluated the in vitro antiviral effect against SARS-CoV-2 of a hepatitis B virus (HBV) hexamer peptide, Poly6, which is capable of eliciting an antiviral effect against human immunodeficiency virus -1 (HIV-1), as a novel HIV-1 integrase inhibitor, and a strong anticancer immune response in an IFN-I-dependent manner, as a novel potential adjuvant in anticancer immunotherapy. Here, we report that Poly6 exerts an anti-SARS-CoV-2 effect, with an estimated 50% inhibitory concentration of 2.617 µM, in the human bronchial epithelial cell line, Calu-3 but not in Vero-E6 cells, which are deficient in type 1 interferon (IFN-I) signaling. We proved via assays based on mRNA profiles, inhibitors, or blocking antibodies that Poly6 can exert an anti-SARS-CoV-2 effect in an IFN-I-dependent manner. We also found that Poly6 inhibits IL-6 production enhanced by SARS-CoV-2 in infected Calu-3 cells at both the transcription and the translation levels, mediated via IL-10 induction in an IFN-I-dependent manner. These results indicate the feasibility of Poly6 as an IFN-I-inducing COVID-19 drug with potent antiviral and anti-inflammatory activities.

Download Full-text

Hepatitis B virus-induced defect of monocyte-derived dendritic cells leads to impaired T helper type 1 response in vitro: mechanisms for viral immune escape

Immunology ◽

10.1046/j.1365-2567.2003.01699.x ◽

2003 ◽

Vol 109 (4) ◽

pp. 487-495 ◽

Cited By ~ 81

Author(s):

Susanne Beckebaum ◽

Vito R. Cicinnati ◽

Xia Zhang ◽

Stanislav Ferencik ◽

andrea Frilling ◽

...

Keyword(s):

Dendritic Cells ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Immune Escape ◽

T Helper ◽

B Virus ◽

Helper Type

Download Full-text

IL-33 Inhibits Hepatitis B Virus through Its Receptor ST2 in Hydrodynamic HBV Mouse Model

Mediators of Inflammation ◽

10.1155/2020/1403163 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Xiuzhu Gao ◽

Xiumei Chi ◽

Xiaomei Wang ◽

Ruihong Wu ◽

Hongqin Xu ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Mouse Model ◽

Hepg2 Cells ◽

Hbv Dna ◽

Dependent Manner ◽

Wild Type ◽

Antiviral Effects ◽

B Virus

Interleukin-33 has been demonstrated to be associated with liver damage. However, its potential value in hepatitis B virus (HBV) infection remains unknown. This study was designed to investigate the role of IL-33 in hydrodynamic HBV mouse model. Different doses of IL-33 were used to treat HBV wild-type, ST2 knockout, CD8+ T depletion, NK depletion C57BL/6 mice and C.B-17 SCID and nod SCID mouse, respectively. The concentrations of HBV DNA, HBsAg, HBeAg, and molecules related to liver function were detected in the collected serum at different time points from model mice. Intrahepatic HBcAg was visualized by immunohistochemical staining of liver tissues. In vitro, hepG2 cells were transfected with pAAV-HBV 1.2, then treated with IL-33. The results showed that IL-33 significantly reduced HBV DNA and HBsAg in a dose-dependent manner in HBV wild-type mice. However, in the IL-33 specific receptor ST2 knockout mice, their antiviral effects could not be exerted. Through immunodeficient animal models and in vivo immune cell depletion mouse model, we found that IL-33 could not play antiviral effects without NK cells. Moreover, IL-33 could reduce the levels of HBsAg and HBeAg in the supernatant of HBV-transfected hepG2 cells in vitro. Our study revealed that IL-33 could inhibit HBV through ST2 receptor in the HBV mouse model, and this effect can be impaired without NK cell. Additionally, IL-33 had the direct anti-HBV effect in vitro, indicating that IL-33 could be a potent inducer of HBV clearance and a promising drug candidate.

Download Full-text

T cells redirected by a chimeric antigen receptor efficiently control Hepatitis B Virus replication in an immunocompetent mouse model

Zeitschrift für Gastroenterologie ◽

10.1055/s-0033-1361054 ◽

2014 ◽

Vol 52 (01) ◽

Author(s):

K Krebs ◽

N Böttinger ◽

LR Huang ◽

M Chmielewski ◽

S Arzberger ◽

...

Keyword(s):

T Cells ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Mouse Model ◽

Virus Replication ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Immunocompetent Mouse ◽

B Virus

Download Full-text

Effects of Dendritic Cells from Hepatitis B Virus Transgenic Mice-Stimulated Autologous Lymphocytes on Hepatitis B Virus Replication: A Study on the Impact of Specific Sensitized Effector Cells on In Vitro Virus Replication

Viral Immunology ◽

10.1089/vim.2014.0053 ◽

2015 ◽

Vol 28 (2) ◽

pp. 85-92 ◽

Cited By ~ 1

Author(s):

Zhong-Yang Shen ◽

Wei-Ping Zheng ◽

Tao Liu ◽

Yang Yang ◽

Hong-Li Song

Keyword(s):

Dendritic Cells ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Transgenic Mice ◽

Virus Replication ◽

Effector Cells ◽

B Virus ◽

The Impact

Download Full-text

Synthesis of 4′-Substituted Purine 2′-Deoxynucleosides and Their Activity against Human Immunodeficiency Virus Type 1 and Hepatitis B Virus

ChemistrySelect ◽

10.1002/slct.201800527 ◽

2018 ◽

Vol 3 (11) ◽

pp. 3313-3317 ◽

Cited By ~ 2

Author(s):

Satoru Kohgo ◽

Shuhei Imoto ◽

Ryoh Tokuda ◽

Yuki Takamatsu ◽

Nobuyo Higashi-Kuwata ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

B Virus ◽

Immunodeficiency Virus

Download Full-text

RMP, a Novel RNA Polymerase II Subunit 5-Interacting Protein, Counteracts Transactivation by Hepatitis B Virus X Protein

Molecular and Cellular Biology ◽

10.1128/mcb.18.12.7546 ◽

1998 ◽

Vol 18 (12) ◽

pp. 7546-7555 ◽

Cited By ~ 65

Author(s):

Dorjbal Dorjsuren ◽

Yong Lin ◽

Wenxiang Wei ◽

Tatsuya Yamashita ◽

Takahiro Nomura ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Rna Polymerase ◽

Rna Polymerase Ii ◽

Binding Protein ◽

Host Protein ◽

Dependent Manner ◽

Binding Region ◽

X Protein ◽

B Virus

ABSTRACT To modulate transcription, regulatory factors communicate with basal transcription factors and/or RNA polymerases in a variety of ways. Previously, it has been reported that RNA polymerase II subunit 5 (RPB5) is one of the targets of hepatitis B virus X protein (HBx) and that both HBx and RPB5 specifically interact with general transcription factor IIB (TFIIB), implying that RPB5 is one of the communicating subunits of RNA polymerase II involved in transcriptional regulation. In this context, we screened for a host protein(s) that interacts with RPB5. By far-Western blot screening, we cloned a novel gene encoding a 508-amino-acid-residue RPB5-binding protein from a HepG2 cDNA library and designated it RPB5-mediating protein (RMP). Expression of RMP mRNA was detected ubiquitously in various tissues. Bacterially expressed recombinant RMP strongly bound RPB5 but neither HBx nor TATA-binding protein in vitro. Endogenous RMP was immunologically detected interacting with assembled RPB5 in RNA polymerase in mammalian cells. The central part of RMP is responsible for RPB5 binding, and the RMP-binding region covers both the TFIIB- and HBx-binding sites of RPB5. Overexpression of RMP, but not mutant RMP lacking the RPB5-binding region, inhibited HBx transactivation of reporters with different HBx-responsive cis elements in transiently transfected cells. The repression by RMP was counteracted by HBx in a dose-dependent manner. Furthermore, RMP has an inhibitory effect on transcriptional activation by VP16 in the absence of HBx. These results suggest that RMP negatively modulates RNA polymerase II function by binding to RPB5 and that HBx counteracts the negative role of RMP on transcription indirectly by interacting with RPB5.

Download Full-text