Toll-Like Receptor 7 Agonist GS-9620 Induces Prolonged Inhibition of HBV in Human Hepatocytes via a Type I Interferon-Dependent Mechanism
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE103325 | GEO | 2018/05/01
REPOSITORIES: GEO
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Project description:Background & Aims: New therapies for chronic hepatitis B (CHB) are urgently needed since current treatments rarely lead to cure. We evaluated whether the oral small molecule toll-like receptor (TLR7) agonist GS-9620 could induce durable anti-viral efficacy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to human hepatitis B virus (HBV). Methods: After evaluating the pharmacokinetics, pharmacodynamics and tolerability of oral GS-9620 in uninfected woodchucks, adult woodchucks chronically infected with WHV (n=7 per group) were dosed with GS-9620 or placebo for 4 or 8 weeks with different treatment schedules. Results: GS?9620 treatment induced rapid, marked and sustained reduction in serum viral DNA (mean maximal 6.2 log10 reduction), and hepatic WHV DNA replicative intermediates, WHV cccDNA and WHV RNA, as well as loss of detectable serum WHV surface antigen (WHsAg). GS-9620 treatment also induced a sustained antibody response against WHsAg in a subset of animals. Strikingly, treatment reduced the incidence of hepatocellular carcinoma (HCC) from 71% in the placebo group to 8% in GS-9620-treated woodchucks with sustained viral load reduction. GS-9620 treatment was associated with reversible increases in serum liver enzymes and thrombocytopenia, and induced intrahepatic CD8+ T cell, NK cell, B cell and interferon (IFN) response transcriptional signatures. Conclusions: The data demonstrate that short duration, finite treatment with the oral TLR7 agonist GS-9620 can induce a sustained antiviral response in the woodchuck model of CHB, and support investigation of this compound as a therapeutic approach to attain a functional cure in CHB patients. Liver biopsies were taken at various time points pre-treatment, during treatment and post-treatment from placebo-treated group and GS9620-treated group (5mg/kg QW). Total RNAs were extracted and analyzed by RNA-Seq. The number of animals analyzed at each time-point for each group was as follows: group 1 (placebo) day -14, n=7; day 43, n=7; day 71, n=7; day 120, n=7; day 250, n=7; group 5 (5 mg/kg QW) day -14, n=7; day 23, n=6; day 57, n=5; day 78, n=4; day 250, n=5.
2015-04-16 | E-GEOD-67935 | biostudies-arrayexpress
Project description:Background & Aims: New therapies for chronic hepatitis B (CHB) are urgently needed since current treatments rarely lead to cure. We evaluated whether the oral small molecule toll-like receptor (TLR7) agonist GS-9620 could induce durable anti-viral efficacy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to human hepatitis B virus (HBV). Methods: After evaluating the pharmacokinetics, pharmacodynamics and tolerability of oral GS-9620 in uninfected woodchucks, adult woodchucks chronically infected with WHV (n=7 per group) were dosed with GS-9620 or placebo for 4 or 8 weeks with different treatment schedules. Results: GS‑9620 treatment induced rapid, marked and sustained reduction in serum viral DNA (mean maximal 6.2 log10 reduction), and hepatic WHV DNA replicative intermediates, WHV cccDNA and WHV RNA, as well as loss of detectable serum WHV surface antigen (WHsAg). GS-9620 treatment also induced a sustained antibody response against WHsAg in a subset of animals. Strikingly, treatment reduced the incidence of hepatocellular carcinoma (HCC) from 71% in the placebo group to 8% in GS-9620-treated woodchucks with sustained viral load reduction. GS-9620 treatment was associated with reversible increases in serum liver enzymes and thrombocytopenia, and induced intrahepatic CD8+ T cell, NK cell, B cell and interferon (IFN) response transcriptional signatures. Conclusions: The data demonstrate that short duration, finite treatment with the oral TLR7 agonist GS-9620 can induce a sustained antiviral response in the woodchuck model of CHB, and support investigation of this compound as a therapeutic approach to attain a functional cure in CHB patients.
2015-04-16 | GSE67935 | GEO
Project description:Background & Aims: In spite of universal vaccination programs, HBV remains a global burden due to the limited therapeutic options available. Therefore, achieving the goal of HBV cure will require a continuous effort to develop novel molecules and combination therapies. In this context, the Toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has shown promising results during its clinical evaluation. Although the effect of SLGN has been explored in the peripheral immune compartment, little is known regarding its intrahepatic response. Therefore, we characterized the transcriptomic changes and intercellular communication events associated with SLGN in the liver microenvironment. Approach & Results: The analysis of single-cell RNA sequencing (scRNA-seq) data allowed us to identify that hepatic TLR8 expression takes place in the myeloid compartment. Therefore, we stablished a method for the isolation of human Kupffer cells (KCs). We found that in vitro treatment of KCs with SLGN induces the upregulation of monocyte markers (e.g., EREG, S100A12) and the downregulation of genes associated with the KC identity (e.g., SPIC, FOLR2). Moreover, treatment of hepatocytes with SLGN-conditioned media (CM) led to the downregulation of NTCP and impaired HBV entry. Finally, co-treatment with SLGN-CM and an IL-6-inhibitory antibody identified this cytokine as mediating the reduced HBV entry. Conclusions: Our results suggest that in addition to its previously described therapeutic activity against HBV, SLGN also presents a prophylactic effect. Furthermore, our characterization of SLGN sheds light into the transcriptional programs regulating KC activation and underscores the importance of considering cell states when annotating cell populations based on scRNA-seq data.
2024-08-10 | GSE240529 | GEO
Project description:Microarray-dependent transcriptional analysis of interferon stimulated genes treated with different kind of interferon subtypes in HBV-infected PHH.
2020-04-20 | GSE138566 | GEO
Project description:Background & Aims: In spite of universal vaccination programs, HBV remains a global burden due to the limited therapeutic options available. Therefore, achieving the goal of HBV cure will require a continuous effort to develop novel molecules and combination therapies. In this context, the Toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has shown promising results during its clinical evaluation. Although the effect of SLGN has been explored in the peripheral immune compartment, little is known regarding its intrahepatic response. Therefore, we characterized the transcriptomic changes and intercellular communication events associated with SLGN in the liver microenvironment. Approach & Results: The analysis of single-cell RNA sequencing (scRNA-seq) data allowed us to identify that hepatic TLR8 expression takes place in the myeloid compartment. Therefore, we stablished a method for the isolation of human Kupffer cells (KCs). We found that in vitro treatment of KCs with SLGN induces the upregulation of monocyte markers (e.g., EREG, S100A12) and the downregulation of genes associated with the KC identity (e.g., SPIC, FOLR2). Moreover, treatment of hepatocytes with SLGN-conditioned media (CM) led to the downregulation of NTCP and impaired HBV entry. Finally, co-treatment with SLGN-CM and an IL-6-inhibitory antibody identified this cytokine as mediating the reduced HBV entry. Conclusions: Our results suggest that in addition to its previously described therapeutic activity against HBV, SLGN also presents a prophylactic effect. Furthermore, our characterization of SLGN sheds light into the transcriptional programs regulating KC activation and underscores the importance of considering cell states when annotating cell populations based on scRNA-seq data.
2024-08-10 | GSE240054 | GEO
Project description:HBV gene expression in HBV-infected primary human hepatocytes.
2022-07-15 | GSE208115 | GEO
Project description:HBV-infected Primary Human Hepatocytes and HBV-infected HepG2-NTCP cells treatment by Interferon subtypes
| PRJNA576399 | ENA
Project description:Human primary hepatocytes isolated from chimeric mice were infected with HBV for 7 days. The comprehensive changes of miRNA levels were determined by miRNA array. MicroRNA expression levels were compared in between control and HBV-replicating primary hepatocytes by 2K microRNA microarrays
2014-03-15 | E-GEOD-55929 | biostudies-arrayexpress
Project description:Monitor HBV mRNA reduction in response to Tazarotene and to identify global transcriptome-wide gene expression associated with Tazarotene treatment in HBV infected PHH using RNA-Seq
2018-09-09 | GSE114003 | GEO
Project description:Purpose: The goal of this study is to identify genes and pathways in macrophages that may be altered by hepatocytes with replicating HBV Methods: THP-1 monocytic cells were treated with PMA for differentiation into macrophages (M0). These macrophages were co-cultured for 4 days with HepAD38 cells with (HBV-) or without (HBV+) the treatmetn of tetracycline and then lysed for the isolation of RNA using NEBNext Ultra II RNA Library Prep Kit for Illumina. The polyA+ RNA-seq was conducted in triplicate, and about 30 million sequence reads per sample that passed quality filters were analyzed by Partek Flow. The qRT–PCR validation of the results was performed using SYBR Green assays. M0 macrophages without co-culturing with HepAD38 cells were also analyzed to serve as the control (M0). Results: To understand how HBV might affect THP-1 macrophages and how macrophages suppressed HBV replication, we conducted the RNA-seq analysis to determine the gene expression profiles in THP-1 macrophages (Mϕ) without co-culturing with HepAD38 cells (M0), THP-1 macrophages co-cultured with HepAD38 cells in the presence of tetracycline (HBV-), and THP-1 macrophages co-cultured with HepAD38 cells in the absence of tetracycline (HBV+). The analysis of RNA-seq results revealed 3946 differentially expressed genes (DEGs) between Mϕ(HBV+) and Mϕ(M0) cells, 3333 DEGs between Mϕ(HBV-) and Mϕ(M0) cells, and 783 DEGs between Mϕ(HBV+) and Mϕ(HBV-) cells (Figure 2A). The heatmap analysis revealed that Mϕ(HBV+) cells expressed significant higher levels of M1 markers including IL-1β and lower levels of M2 markers than in Mϕ(HBV-) cells (Figure 2B). The induction of IL-1β in Mϕ(HBV+) cells was also highly prominent when the cytokine expression profiles were analyzed by the volcano plot (Figure 2C). This induction of IL-1β was confirmed by RT-qPCR analysis (Figure S2E). These results indicated that THP-1 macrophages co-cultured with cells containing replicating HBV would undergo the M1 polarization. Interestingly, the heat map analysis of top 20 DEGs, based on low false discovery rate and high Log2 fold changes, between Mϕ(HBV+) and Mϕ(HBV-) cells revealed that seven of them were mitochondria-encoded genes that regulate the OXPHOS (Figure 2D). The pathway analysis indicated that the OXPHOS pathway was indeed upregulated in MΦ(HBV+) cells, although some pathways in these cells were also downregulated (e.g., Sirtuin signaling) and some were not affected (e.g., insulin receptor signaling) (Figure 2E). Conclusions: Our study provided the detailed analysis of the response of macrophages to hepatocytes containing replicating HBV. Our results indicated that HBV-could induce the M1 polarization of THP-1-derived macrophage. The induction of CXCL1 expression in macrophages by HBV likely plays an important role in the hepatic infiltration of neutrophils, whih express a high level of CXCR1 , the receptor of CXCL1. Our finding of an increased expression of mitochondria-encoded genes that regulate OXPHOS also suggested that HBV might promote OXPHOS in macrophages.
2022-02-18 | GSE179618 | GEO