Targeting lipid biosynthesis pathways for hepatitis B virus cure

Hyrina, Anastasia; Burdette, Dara; Song, Zhijuan; Ramírez, Ricardo; Okesli-Armlovich, Ayse; Vijayakumar, Archana; Bates, Jamie; Trevaskis, James L.; Fletcher, Simon P.; Lee, William A.; Holdorf, Meghan

doi:10.1371/journal.pone.0270273

Cited by 12 publications

(6 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that silencing CTCF resulted in the upregulation of n =544 genes, which were associated with several pathways that are exploited by HBV. Fatty acid and bile acid metabolism are hepatocyte specific functions and represent the most significantly upregulated pathways and factors within these gene sets that are being actively explored as therapeutic targets for HBV cure (as reviewed in [52]). In contrast, the most significantly downregulated pathways were genes that are under the transcriptional control of Myc.…”

Section: Discussionmentioning

confidence: 99%

CTCF regulates hepatitis B virus cccDNA chromatin topology

Dobrica,

Varghese,

Harris

et al. 2024

Journal of General Virology

View full text Add to dashboard Cite

Hepatitis B Virus (HBV) is a small DNA virus that replicates via an episomal covalently closed circular DNA (cccDNA) that serves as the transcriptional template for viral mRNAs. The host protein, CCCTC-binding factor (CTCF), is a key regulator of cellular transcription by maintaining epigenetic boundaries, nucleosome phasing, stabilisation of long-range chromatin loops and directing alternative exon splicing. We previously reported that CTCF binds two conserved motifs within Enhancer I of the HBV genome and represses viral transcription, however, the underlying mechanisms were not identified. We show that CTCF depletion in cells harbouring cccDNA-like HBV molecules and in de novo infected cells resulted in an increase in spliced transcripts, which was most notable in the abundant SP1 spliced transcript. In contrast, depletion of CTCF in cell lines with integrated HBV DNA had no effect on the abundance of viral transcripts and in line with this observation there was limited evidence for CTCF binding to viral integrants, suggesting that CTCF-regulation of HBV transcription is specific to episomal cccDNA. Analysis of HBV chromatin topology by Assay for Transposase Accessible Chromatin Sequencing (ATAC-Seq) revealed an accessible region spanning Enhancers I and II and the basal core promoter (BCP). Mutating the CTCF binding sites within Enhancer I resulted in a dramatic rearrangement of chromatin accessibility where the open chromatin region was no longer detected, indicating loss of the phased nucleosome up- and down-stream of the HBV enhancer/BCP. These data demonstrate that CTCF functions to regulate HBV chromatin conformation and nucleosomal positioning in episomal maintained cccDNA, which has important consequences for HBV transcription regulation.

show abstract

Section: Discussionmentioning

confidence: 99%

CTCF regulates hepatitis B virus cccDNA chromatin topology

Dobrica,

Varghese,

Harris

et al. 2024

Journal of General Virology

View full text Add to dashboard Cite

show abstract

“…The exact contribution of immunity factors in the antiviral effect of these drugs needs to be further explored, and whether this general concept can be translated in vivo has to be determined. Lipid and cholesterol biosynthesis pathways are also considered as therapeutic targets in the treatment of HBV based on observations that drugs inhibiting these pathways decrease the production of subviral and/or viral particles ( 75 , 204 ). Interestingly, serum lipid profiles change in HCV-infected patients treated with direct-acting antivirals (DAA) and this correlates with viral clearance ( 205 , 206 ).…”

Section: Discussionmentioning

confidence: 99%

What role for cellular metabolism in the control of hepatitis viruses?

Diaz

Vidalain²,

Ramière³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Hepatitis B, C and D viruses (HBV, HCV, HDV, respectively) specifically infect human hepatocytes and often establish chronic viral infections of the liver, thus escaping antiviral immunity for years. Like other viruses, hepatitis viruses rely on the cellular machinery to meet their energy and metabolite requirements for replication. Although this was initially considered passive parasitism, studies have shown that hepatitis viruses actively rewire cellular metabolism through molecular interactions with specific enzymes such as glucokinase, the first rate-limiting enzyme of glycolysis. As part of research efforts in the field of immunometabolism, it has also been shown that metabolic changes induced by viruses could have a direct impact on the innate antiviral response. Conversely, detection of viral components by innate immunity receptors not only triggers the activation of the antiviral defense but also induces in-depth metabolic reprogramming that is essential to support immunological functions. Altogether, these complex triangular interactions between viral components, innate immunity and hepatocyte metabolism may explain why chronic hepatitis infections progressively lead to liver inflammation and progression to cirrhosis, fibrosis and hepatocellular carcinoma (HCC). In this manuscript, we first present a global overview of known connections between the innate antiviral response and cellular metabolism. We then report known molecular mechanisms by which hepatitis viruses interfere with cellular metabolism in hepatocytes and discuss potential consequences on the innate immune response. Finally, we present evidence that drugs targeting hepatocyte metabolism could be used as an innovative strategy not only to deprive viruses of key metabolites, but also to restore the innate antiviral response that is necessary to clear infection.

show abstract

Section: Summary and Prospectmentioning

confidence: 94%

“…Liver-targeted ACC inhibitors effectively inhibit the secretion of hepatitis B surface antigens in HBV-infected HepG 2-NTCP cells. However, these inhibitors do not show antiviral activity in HBV-infected chimeric mice with humanized liver [186]. When ACC activity is inhibited in mice, lipids derived from the lipolysis pathway or diet may satisfy HBsAg production.…”

Section: Summary and Prospectmentioning

confidence: 99%

Oncogenic viruses and host lipid metabolism: a new perspective

Gong

Zhang

Wen

et al. 2023

Journal of General Virology

View full text Add to dashboard Cite

As noncellular organisms, viruses do not have their own metabolism and rely on the metabolism of host cells to provide energy and metabolic substances for their life cycles. Increasing evidence suggests that host cells infected with oncogenic viruses have dramatically altered metabolic requirements and that oncogenic viruses produce substances used for viral replication and virion production by altering host cell metabolism. We focused on the processes by which oncogenic viruses manipulate host lipid metabolism and the lipid metabolism disorders that occur in oncogenic virus-associated diseases. A deeper understanding of viral infections that cause changes in host lipid metabolism could help with the development of new antiviral agents as well as potential new therapeutic targets.

show abstract

Targeting lipid biosynthesis pathways for hepatitis B virus cure

Cited by 12 publications

References 54 publications

CTCF regulates hepatitis B virus cccDNA chromatin topology

CTCF regulates hepatitis B virus cccDNA chromatin topology

What role for cellular metabolism in the control of hepatitis viruses?

Oncogenic viruses and host lipid metabolism: a new perspective

Contact Info

Product

Resources

About