Single hepatocytes show persistence and transcriptional inactivity of hepatitis B

Balagopal, Ashwin; Grudda, Tanner; Ribeiro, Ruy M.; Saad, Yasmeen; Hwang, Hyon S.; Quinn, Jeffrey; Murphy, Michael; Ward, Kathleen; Sterling, Richard K.; Zhang, Yang; Perelson, Alan S.; Sulkowski, Mark S.; Osburn, William O.; Thio, Chloe L.

doi:10.1172/jci.insight.140584

Cited by 26 publications

(35 citation statements)

References 27 publications

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“…For these values of

, the model always displays the two-phase behaviour ( Figure 3 d), suggesting that it is biologically significant. In HBV/HIV coinfection, it has been observed that the number of cccDNAs can sometimes be as high as 10–16 cccDNAs per cell [ 69 ] (although the median was still found to be one). However, due to the complexity of these coinfections, this is beyond the scope of this model.…”

Section: Resultsmentioning

confidence: 99%

An Intracellular Model of Hepatitis B Viral Infection: An In Silico Platform for Comparing Therapeutic Strategies

Fatehi

Bingham

Dykeman

et al. 2020

Viruses

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Hepatitis B virus (HBV) is a major focus of antiviral research worldwide. The International Coalition to Eliminate HBV, together with the World Health Organisation (WHO), have prioritised the search for a cure, with the goal of eliminating deaths from viral hepatitis by 2030. We present here a comprehensive model of intracellular HBV infection dynamics that includes all molecular processes currently targeted by drugs and agrees well with the observed outcomes of several clinical studies. The model reveals previously unsuspected kinetic behaviour in the formation of sub-viral particles, which could lead to a better understanding of the immune responses to infection. It also enables rapid comparative assessment of the impact of different treatment options and their potential synergies as combination therapies. A comparison of available and currently developed treatment options reveals that combinations of multiple capsid assembly inhibitors perform best.

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“…For these values of

Section: Resultsmentioning

confidence: 99%

An Intracellular Model of Hepatitis B Viral Infection: An In Silico Platform for Comparing Therapeutic Strategies

Fatehi

Bingham

Dykeman

et al. 2020

Viruses

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“…The post-RNAi treatment reduction of HBeAg, HBcrAg and HBV RNA in initially HBeAg-positive patients with high viremia indicates expression from cccDNA was reduced. This reduction could be due to cccDNA loss, to silencing of expression or both [ 43 ]. The episomal HBV cccDNA is much like plasmid DNA.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism whereby replication returns to baseline levels following the end of a treatment has been called “replication memory.” Further study is required to understand if this replication memory is the result of reactivated cccDNA following alleviation of RNAi-suppressed core and X protein expression, for example. A preferable result of treatment would be loss of cccDNA, but this step is slow [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, two recent reports demonstrated that long-term NUC treatment results in loss of HBV DNA, both cccDNA and integrated HBV [ 51 , 52 ]. Although the percentages of patients able to reach functional cure through NUCs or PEG-IFN treatment are low, this process typically takes years [ 43 ]. The length of time may be due to the importance of slow replacement of hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

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RNA Interference Therapy for Chronic Hepatitis B Predicts the Importance of Addressing Viral Integration When Developing Novel Cure Strategies

Wooddell

Gehring

Yuen

et al. 2021

Viruses

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Chronic hepatitis B infection remains a globally important cause of morbidity and mortality and has recently undergone a renaissance in therapeutic interest with increased pre-clinical and clinical testing of new drug classes. One of the first new classes in the clinic was RNA interference agents, which have the potential to impact the entire viral life cycle by reducing all virus-produced mRNA. Early clinical testing with the first of these agents in the clinic, ARC-520, demonstrated that rapid and deep reductions in viral proteins, RNA and DNA could be produced with this approach, but also the surprising insight that HBsAg production from incomplete HBV DNA integrated into the host genome appears to play a heretofore unappreciated and important role in maintaining circulating HBsAg, thought to play a fundamental role in preventing host clearance of the virus. Thus, accounting for viral DNA integration in novel HBV treatment approaches may prove to be essential to achieving successful finite therapies of this difficult to treat chronic infection.

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“…The function of CIC in mammalian development is less well-understood, but CIC has emerged as an important regulator of neuronal maturation during early brain development. Pan-neural ( Nestin-Cre ) Cic knockout mice die by weaning age with prominent maturation defects in cortical neurons and dentate gyrus granule neurons 11 . Neocortical excitatory neurons in the Emx1-Cre Cic knockout mice, which lack Cic in forebrain excitatory neurons and glia, have reduced post-mitotic survival and the surviving neurons develop abnormal dendritic arborization 12 .…”

Section: Introductionmentioning

confidence: 99%

Capicua regulates the development of adult-born neurons in the hippocampus

Hourigan

Balay

Yee

et al. 2021

Sci Rep

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New neurons continuously arise from neural progenitor cells in the dentate gyrus of the adult hippocampus to support ongoing learning and memory formation. To generate functional adult-born neurons, neural progenitor cells proliferate to expand the precursor cell pool and differentiate into neurons. Newly generated cells then undergo postmitotic maturation to migrate to their final destination and develop elaborate dendritic branching, which allows them to receive input signals. Little is known about factors that regulate neuronal differentiation, migration, and dendrite maturation during adult hippocampal neurogenesis. Here, we show that the transcriptional repressor protein capicua (CIC) exhibits dynamic expression in the adult dentate gyrus. Conditional deletion of Cic from the mouse dentate gyrus compromises the adult neural progenitor cell pool without altering their proliferative potential. We further demonstrate that the loss of Cic impedes neuronal lineage development and disrupts dendritic arborization and migration of adult-born neurons. Our study uncovers a previously unrecognized role of CIC in neurogenesis of the adult dentate gyrus.

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Single hepatocytes show persistence and transcriptional inactivity of hepatitis B

Cited by 26 publications

References 27 publications

An Intracellular Model of Hepatitis B Viral Infection: An In Silico Platform for Comparing Therapeutic Strategies

An Intracellular Model of Hepatitis B Viral Infection: An In Silico Platform for Comparing Therapeutic Strategies

RNA Interference Therapy for Chronic Hepatitis B Predicts the Importance of Addressing Viral Integration When Developing Novel Cure Strategies

Capicua regulates the development of adult-born neurons in the hippocampus

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