Mathematical Modeling for Hepatitis B Virus: Would Spatial Effects Play a Role and How to Model It?

Means, Shawn; Ali, A.; Ho, Harvey; Heffernan, Jane M.

doi:10.3389/fphys.2020.00146

Cited by 10 publications

(7 citation statements)

References 32 publications

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“…For understanding infection dynamics in the liver, establishing the importance of liver structure, and its distinctive spatial organization in the sinusoids is only the beginning of a multiscale HBV mathematical model (S. Means et al, 2020). Experimental observations on hepatocytes studied in cultured populations often lose their identity, as these hepatocytes are without the influence of surrounding spatial structures and fluid flows (Ortega-Prieto et al, 2018).…”

Section: Models For Hepatitismentioning

confidence: 99%

“…Therefore, a patient's age and body weight need to be considered for drug dosage to account for the F I G U R E 6 Multiscale models for HBV integrates sinusoidal flow models with HBV dynamic model. They aim to simulate (a) the spatial uptake difference along metabolic zones in sinusoids due to heterogeneous distribution of innate immune cells at key spatial locations (e.g., Kupffer near portal-triads), the polarity of cellular distributions of sinusoid-facing transporters, for example, NTCP, and (b) the treatment mechanism through interferon (Cangelosi et al, 2017;S. Means et al, 2020) differences in metabolism between adults and children.…”

Section: Pharmacokinetic Models For the Livermentioning

confidence: 99%

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In silico modeling for the hepatic circulation and transport: From the liver organ to lobules

Means

Safaei

et al. 2022

WIREs Mechanisms of Disease

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The function of the liver depends critically on its blood supply. Numerous in silico models have been developed to study various aspects of the hepatic circulation, including not only the macro-hemodynamics at the organ level, but also the microcirculation at the lobular level. In addition, computational models of blood flow and bile flow have been used to study the transport, metabolism, and clearance of drugs in pharmacokinetic studies.These in silico models aim to provide insights into the liver organ function under both healthy and diseased states, and to assist quantitative analysis for surgical planning and postsurgery treatment. The purpose of this review is to provide an update on state-of-the-art in silico models of the hepatic circulation and transport processes. We introduce the numerical methods and the physiological background of these models. We also discuss multiscale frameworks that have been proposed for the liver, and their linkage with the large context of systems biology, systems pharmacology, and the Physiome project.

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Section: Models For Hepatitismentioning

confidence: 99%

Section: Pharmacokinetic Models For the Livermentioning

confidence: 99%

In silico modeling for the hepatic circulation and transport: From the liver organ to lobules

Means

Safaei

et al. 2022

WIREs Mechanisms of Disease

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“…The spatial degrees of freedom have been shown to be a crucial aspect for infection at different scales. 8,27 The following biological events were modeled: 0. The viral capsid diffuses in the cytoplasm until reaching an NPC 1.…”

Section: Kinetic Model For the Hbv Infectionmentioning

confidence: 99%

A Spatial Whole-Cell Model for Hepatitis B Viral Infection and Drug Interactions

Ghaemi

Gruebele

2022

Preprint

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Despite a vaccine, hepatitis B remains a world-wide source of infections and deaths, and tackling the infection requires a multimodal approach against the virus. We develop a whole-cell model combining spatial and kinetic models for the infection cycle of a hepatocyte by hepatitis B virus (HBV). We simulate a near complete viral infection cycle with this whole cell model stochastically for 10 minutes of biological time, as a starting point to map out virus-host interaction. We find that with an established infection, decreasing the copy number of envelope proteins can shift the dominant infection pathways to amplification, resulting in higher cccDNA copy number, which may be a mode of action for siRNA drugs. Capsid mutants when destabilized such that they disassemble at nuclear pore complexes lead to increase in cccDNA copy number, but a cytoplasmic disassembly does not increase cccDNA copy number. Finally, our simulations can predict the best drug dosage and timing of administration. Our adaptable computational platform can be utilized to study other viruses and host-virus interactions.

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“…Liver infection with hepatitis B is a life-threatening disease–causing hepatocellular carcinoma, liver cirrhosis, liver damage and failure with an estimated death total of at least 887, 000 worldwide each year ( Elgouhari et al., 2008 ; Tarao et al., 2019 ; World Health Organization, 2015 ). About 250 million people worldwide suffer from chronic hepatitis B virus (HBV) infection, and few effective treatment options exist ( Aparna et al., 2015 ; Means et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Global sensitivity analysis of a single-cell HBV model for viral dynamics in the liver

Ali

Means

et al. 2021

Infectious Disease Modelling

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The predictive accuracy of mathematical models representing anything ranging from the meteorological to the biological system profoundly depends on the quality of model parameters derived from experimental data. Hence, robust sensitivity analysis (SA) of these critical model parameters aids in sifting the influential from the negligible out of typically vast parameter regimes, thus illuminating key components of the system under study. We here move beyond traditional local sensitivity analysis to the adoption of global SA techniques. Partial rank correlation coefficient (PRCC) based on Latin hypercube sampling is compared with the variance-based Sobol method. We selected for this SA investigation an infection model for the hepatitis-B virus (HBV) that describes infection dynamics and clearance of HBV in the liver [Murray & Goyal, 2015]. The model tracks viral particles such as the tenacious and nearly ineradicable covalently closed circular DNA (cccDNA) embedded in infected nuclei and an HBV protein known as p36. Our application of these SA methods to the HBV model illuminates, especially over time, the quantitative relationships between cccDNA synthesis rate and p36 synthesis and export. Our results reinforce previous observations that the viral protein, p36, is by far the most influential factor for cccDNA replication. Moreover, both methods are capable of finding crucial parameters of the model. Though the Sobol method is independent of model structure (e.g., linearity and monotonicity) and well suited for SA, our results ensure that LHS-PRCC suffices for SA of a non-linear model if it is monotonic.

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Mathematical Modeling for Hepatitis B Virus: Would Spatial Effects Play a Role and How to Model It?

Cited by 10 publications

References 32 publications

In silico modeling for the hepatic circulation and transport: From the liver organ to lobules

In silico modeling for the hepatic circulation and transport: From the liver organ to lobules

A Spatial Whole-Cell Model for Hepatitis B Viral Infection and Drug Interactions

Global sensitivity analysis of a single-cell HBV model for viral dynamics in the liver

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