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Characterization of Hepatitis B Virus Transcripts in Chronically HBV-infected Chimpanzees and Patients Treated with ARC-520 siRNA Demonstrates Transcriptional Silencing of cccDNA

ABSTRACT: Characterization of Hepatitis B Virus Transcripts in Chronically HBV-infected Chimpanzees and Patients Treated with ARC-520 siRNA Demonstrates Transcriptional Silencing of cccDNA

PROVIDER: PRJNA1175645 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31060854_subreads.fastq.gz	Fastqsanger.gz
	SRR31060855_subreads.fastq.gz	Fastqsanger.gz
	SRR31060856_subreads.fastq.gz	Fastqsanger.gz
	SRR31060857_subreads.fastq.gz	Fastqsanger.gz
	SRR31060858_subreads.fastq.gz	Fastqsanger.gz

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Characterization of Hepatitis B Virus Transcripts in Chronically HBV-infected Chimpanzees and Patients Treated with ARC-520 siRNA Demonstrates Transcriptional Silencing of cccDNA

Project description:Full-length hepatitis B virus (HBV) transcripts of chimpanzees and patients treated with multidose (MD) HBV siRNA ARC-520 and entecavir (ETV) were characterized by single-molecule real-time (SMRT) sequencing, identifying multiple types of transcripts with the potential to encode HBx, HBsAg, HBeAg, core, and polymerase, as well as transcripts likely to be derived from dimers of dslDNA, and these differed between HBeAg-positive (HBeAg+) and HBeAg-negative (HBeAg−) individuals. HBV transcripts from the last follow-up ~30 months post-ARC-520 treatment were categorized from one HBeAg+ (one of two previously highly viremic patients that became HBeAg− upon treatment and had greatly reduced cccDNA products) and four HBeAg− patients. The previously HBeAg+ patient received a biopsy that revealed that he had 3.4 copies/cell cccDNA (two to three orders of magnitude more cccDNA than HBeAg− chimpanzees) but expressed primarily truncated X and HBsAg from iDNA, like two patients that were HBeAg− at the start of the study and had one copy/cell cccDNA. No HBV transcripts were detected in two other HBeAg− patients that had ~0.3 copies/cell cccDNA, one of which had seroconverted for HBsAg. The paucity of cccDNA-derived transcripts in the presence of high cccDNA demonstrates the transcriptional silencing of HBV following MD siRNA treatment with ETV.

2024-12-17 | GSE279971 | GEO

Binding of Nucleolin to HBV cccDNA

Project description:Covalently closed circular DNA (cccDNA) forms the basis for replication and persistence of hepatitis B virus (HBV) in the chronically infected liver. In this study we sought to identify host factors interacting with the HBV genome. Nucleolin (Ncl) was identified as a potential interactor of HBV cccDNA. This interaction was veriefied using an established ChIPseq protocol. The data show that Ncl binds cccDNA albeit at lower levels than HBcAg. Ncl deposition occurs across the genome without a clear localization and a variable pattern of deposition between experiments. This verifies the interaction of Ncl with HBV-cccDNA.

2021-12-31 | GSE123715 | GEO

Hepatitis B virus core protein is not required for cccDNA transcriptional regulation

Project description:Background & Aims: Hepatitis B virus (HBV) infection is a major health burden worldwide and currently there is no cure. The persistence of HBV covalently closed circular DNA (cccDNA) is the major obstacle for antiviral treatment. HBV core protein (HBc) has merged as a promising antiviral target, as it plays important roles in critical steps of viral life cycle. However, whether HBc could regulate HBV cccDNA transcription remains to be illustrated. Methods: Synthesized HBV cccDNA and HBVcircle with or without HBc deficiency were transfected into hepatocytes. A recently reported Adeno-Associated Virus (AAV) mediated HBV cccDNA mouse model was employed. Two capsid assembly modulators (CAMs) were used. HBV replication markers were evaluated. Chromatin immunoprecipitation (ChIP) or ChIP sequencing assays were conducted with different transcription factors, histones and RNA polymerase 2. Results: In HBV cccDNA and HBVcircle transfection assays, lack of HBc showed no effect on transcription of HBV RNA as well as HBV surface antigen production. Reconstitution of HBc did not change cccDNA derived HBV markers. Similar results were obtained in vivo, from mouse cccDNA model. ChIP data revealed similar transcription regulation of HBc deficient cccDNA chromatin with wide type cccDNA. Furthermore, CAMs treatment could not alter cccDNA transcription. Conclusions: Our results indicate that HBc neither affects histone modifications and transcription factors binding of cccDNA, nor influences cccDNA transcription. Although CAMs could reduce HBc binding to cccDNA, it does not suppress cccDNA transcriptional activity. Thus, therapeutic targeting capsid or HBc is not sufficient to reduce cccDNA transcription.

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Interferon-induced degradation of the hepatitis B virus persistence form, cccDNA, depends on ISG20

Project description:Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that cannot be targeted by available antivirals. Cytokine treatments can diminish HBV cccDNA via APOBEC3-mediated deamination. Here we show that overexpression of APOBEC3A alone, however, was not sufficient to reduce cccDNA in HBV-infected cells. This required addition of interferon indicating that cccDNA degradation requires an additional, interferon-stimulated gene (ISG). Transcriptome analyses identified ISG20 as the only type I and II interferon-induced, nucleus-resident protein with annotated nuclease activity. ISG20 expression was detected in human livers in acute, self-limiting but not in chronic hepatitis B. ISG20 depletion abolished the interferon-induced loss of cccDNA, and co-expression of ISG20 and APOBEC3A was sufficient to diminish cccDNA. In conclusion, non-cytolytic HBV cccDNA decline requires induction of a deaminase and nuclease. Our findings highlight that ISGs cooperate for their antiviral function and this cooperativity may be explored for therapeutic targeting.

2021-04-22 | PXD019285 | Pride

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Age-Associated Epigenetic Change in Chimpanzees and Humans

Project description:Genome wide DNA methylation profiling of captive chimpanzees of ages spanning the chimpanzee lifespan (whole blood) Methylation levels have been shown to change with age at sites across the human genome. Change at some of these sites is so consistent across individuals that it can be used as an “epigenetic clock” to predict an individual’s chronological age within a few years. Studies of age-related epigenetic change in other mammals, including mice, whales, and canids, show that some but not all of the same loci as in humans undergo age-associated methylation changes. An in-depth comparison of chimpanzees with humans is of interest because the two species are genetically similar but differ in lifespan. To this end, we profiled genome-wide blood methylation levels for 113 samples from 83 chimpanzees aged 1-58 years (26 chimpanzees were sampled at multiple ages during their lifespan). We used this data to build a chimpanzee-specific epigenetic clock model as well as to compare genome-wide patterns of change with age between humans and chimpanzees more generally.

2020-08-23 | GSE136296 | GEO

Identification of ISG20 as the nuclease involved in interferon-induced decline of hepatitis B virus cccDNA

Project description:Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus that cannot be targeted by available antivirals. Cytokine treatments can purge cccDNA from the nucleus of infected cells by APOBEC3-mediated deamination. cccDNA levels in HBV-infected cells were not reduced by overexpression of APOBEC3A alone, but only after simultaneous addition of interferon. This indicated the need of an additional, interferon-induced factor (ISG). Microarray analysis identified ISG20 as the only nuclease located to the nucleus induced by type I and II interferons. ISG20 was confirmed to be expressed in acute, self-limiting but not in chronic hepatitis B in human livers. ISG20 knockdown abolished the interferon-induced loss of cccDNA, and co-expression of ISG20 and APOBEC3A was sufficient to diminish cccDNA without further treatment. To conclude, nucleolar ISG20 was identified as the nuclease contributing to interferon-induced purging of HBV cccDNA, opening new avenues for antiviral targeting.

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