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:BACKGROUND & AIMS:Direct-acting antiviral agents suppress hepatitis B virus (HBV) load, but they require life-long use. Stimulation of the innate immune system could increase its ability to control the virus and have long-lasting effects after a finite regimen. We investigated the effects of immune activation with GS-9620--a potent and selective orally active small molecule agonist of Toll-like receptor 7--in chimpanzees with chronic HBV infection. METHODS:GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1-week rest, for 4 weeks at 2 mg/kg. We measured viral load in plasma and liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters: interferon-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored to determine the safety and tolerability of GS-9620. RESULTS:Short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. The mean maximum reduction of viral DNA was 2.2 logs, which occurred within 1 week of the end of GS-9620 administration; reductions of >1 log persisted for months. Serum levels of HBV surface antigen and HBV e antigen, and numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased. GS-9620 administration induced production of interferon-? and other cytokines and chemokines, and activated interferon-stimulated genes, natural killer cells, and lymphocyte subsets. CONCLUSIONS:The small molecule GS-9620 activates Toll-like receptor 7 signaling in immune cells of chimpanzees to induce clearance of HBV-infected cells. This reagent might be developed for treatment of patients with chronic HBV infection.
| S-EPMC3691056 | biostudies-literature