Hepatitis B virus persistence and reactivation

Shi, Yu; Zheng, Ming‐Hua

doi:10.1136/bmj.m2200

Cited by 113 publications

(104 citation statements)

References 202 publications

(319 reference statements)

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“…As a type of DNA molecule, circular DNA is ubiquitous in nature and includes bacterial plasmids as well as some viral genomes [ 1 – 3 ]. More than half a century ago, researchers found that there is also a special class of circular DNA in eukaryotes, which is isolated from the normal genome, free from the chromosomal genome and participates in physiological or pathological processes in special ways [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Extrachromosomal circular DNA: a new potential role in cancer progression

et al. 2021

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Extrachromosomal circular DNA (eccDNA) is considered a circular DNA molecule that exists widely in nature and is independent of conventional chromosomes. eccDNA can be divided into small polydispersed circular DNA (spcDNA), telomeric circles (t-circles), microDNA, and extrachromosomal DNA (ecDNA) according to its size and sequence. Multiple studies have shown that eccDNA is the product of genomic instability, has rich and important biological functions, and is involved in the occurrence of many diseases, including cancer. In this review, we focus on the discovery history, formation process, characteristics, and physiological functions of eccDNAs; the potential functions of various eccDNAs in human cancer; and the research methods employed to study eccDNA.

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Section: Introductionmentioning

confidence: 99%

Extrachromosomal circular DNA: a new potential role in cancer progression

et al. 2021

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“…Chronic hepatitis B virus (HBV) infection remains a major global health burden, with 350 million chronically infected individuals worldwide (1,2). In addition to hepatocellular carcinoma (HCC) and decompensated cirrhosis, acute-onchronic liver failure (ACLF) is another cause of death in patients with chronic HBV infection (3).…”

Section: Introductionmentioning

confidence: 99%

Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure

Wu¹,

Sun²,

Wang³

et al. 2021

Front. Immunol.

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Background and AimsAcute-on-chronic liver failure (ACLF) is characterized by systemic inflammation accompanied by defective anti-bacterial immunity. The role of neutrophils in immune derangement of ACLF has not been fully elucidated. This study is aimed to characterize the role of circulating neutrophils in HBV-related ACLF patients.MethodsQuantitative, phenotypic, transcriptomic, and functional alterations of circulating neutrophils were compared in ACLF and non-ACLF subjects and analyzed for associations with short-term outcomes. Interventional experiments were performed to test the impact on ACLF-patient neutrophil function in vitro.ResultsCirculating absolute neutrophil count was significantly increased in patients with ACLF and was an independent risk factor for 28-day mortality. ACLF-patient neutrophils differentially expressed a panel of surface markers (include TLR-1, TLR-2, TLR-4, CEACAM-1 and FPR1), as well as a distinct transcriptomic signature. ACLF-neutrophils displayed significantly impaired phagocytosis but an increased capacity to form neutrophil extracellular traps (NETs), which was more pronounced in patients with poor outcome. Healthy neutrophils mimicked functional characteristics of ACLF counterpart after co-cultured with plasma from ACLF patients. The oxidative burst and cytokine production capacities remained unchanged. Plasma GM-CSF, IL-6, IL-8, IL-10, and IP-10 levels, as well as lipopolysaccharide (LPS) concentration, were markedly elevated in ACLF patients but not DAMP molecules HMGB-1 and HSP70. Finally, a glycolysis inhibitor, 2-deoxy-glucose, reduced NET formation of ACLF patients’ neutrophils.ConclusionsCirculating ACLF-patient neutrophils exhibit alterations in number, phenotype, gene expression and function, which was associated with poor outcome and shaped by the ACLF circulatory environment. Inhibiting glycolysis can reverse neutrophil dysfunction in ACLF patients.

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“…Virus replication may return to normal levels at any time after drug withdrawal or drug resistance occurs ( Zoulim and Locarnini, 2009 ; Deng and Tang, 2011 ). cccDNA serves as a template for the transcription of viral RNAs through employing the cellular transcription machinery ( Rall et al, 1983 ; Shi and Zheng, 2020 ), which is resistant to common antiviral therapies. The key challenge is the persistence of cccDNA in infected hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Hepatitis B Virus by AAV8-Derived CRISPR/SaCas9 Expressed From Liver-Specific Promoters

et al. 2021

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Curative therapies for chronic hepatitis B virus (HBV) infection remain a distant goal, and the persistence of stable covalently closed circular DNA (cccDNA) during HBV replication is a key barrier that is hard to break through using the drugs currently approved for HBV treatment. Due to the accuracy, efficiency, and cost-effectiveness of genome editing, CRISPR/Cas technologies are being widely used for gene therapy and in antiviral strategies. Although CRISPR/Cas could possibly clear cccDNA, ensuring its safety is requirement for application. In our study, we analyzed the liver specificity of several promoters and constructed candidate promoters in the CRISPR/Staphylococcus aureus Cas9 (SaCas9) system combined with hepatotropic AAV8 (whereby AAV refers to adeno-associated virus) to verify the efficacy against HBV. The results revealed that the reconstructed CRISPR/SaCas9 system in which the original promoter replaced with a liver-specific promoter could still inhibit HBV replication both in vitro and in vivo. Three functional guide RNAs (gRNAs), T2, T3, and T6, which target the conserved regions of different HBV genotypes, demonstrated consistently better anti-HBV effects with different liver-specific promoters. Moreover, the three gRNAs inhibited the replication of HBV genotypes A, B, and C to varying degrees. Under the action of the EnhII-Pa1AT promoter and AAV8, the expression of SaCas9 was further decreased in other organs or tissues in comparison to liver. These results are helpful for clinical applications in liver by ensuring the effects of the CRISPR/Cas9 system remain restricted to liver and, thereby, reducing the probability of undesired and harmful effects through nonspecific targeting in other organs.

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Hepatitis B virus persistence and reactivation

Cited by 113 publications

References 202 publications

Extrachromosomal circular DNA: a new potential role in cancer progression

Extrachromosomal circular DNA: a new potential role in cancer progression

Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure

Inhibition of Hepatitis B Virus by AAV8-Derived CRISPR/SaCas9 Expressed From Liver-Specific Promoters

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