A multi-scale spatial model of hepatitis-B viral dynamics.

Quentin Cangelosi,Shawn A Means,Harvey Ho

doi:10.1371/journal.pone.0188209

Quentin Cangelosi, Shawn A Means + Show 1 more

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https://doi.org/10.1371/journal.pone.0188209

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Abstract

Chronic hepatitis B viral infection (HBV) afflicts around 250 million individuals globally and few options for treatment exist. Once infected, the virus entrenches itself in the liver with a notoriously resilient colonisation of viral DNA (covalently-closed circular DNA, cccDNA). The majority of infections are cleared, yet we do not understand why 5% of adult immune responses fail leading to the chronic state with its collateral morbid effects such as cirrhosis and eventual hepatic carcinoma. The liver environment exhibits particularly complex spatial structures for metabolic processing and corresponding distributions of nutrients and transporters that may influence successful HBV entrenchment. We assembled a multi-scaled mathematical model of the fundamental hepatic processing unit, the sinusoid, into a whole-liver representation to investigate the impact of this intrinsic spatial heterogeneity on the HBV dynamic. Our results suggest HBV may be exploiting spatial aspects of the liver environment. We distributed increased HBV replication rates coincident with elevated levels of nutrients in the sinusoid entry point (the periportal region) in tandem with similar distributions of hepatocyte transporters key to HBV invasion (e.g., the sodium-taurocholate cotransporting polypeptide or NTCP), or immune system activity. According to our results, such co-alignment of spatial distributions may contribute to persistence of HBV infections, depending on spatial distributions and intensity of immune response as well. Moreover, inspired by previous HBV models and experimentalist suggestions of extra-hepatic HBV replication, we tested in our model influence of HBV blood replication and observe an overall nominal effect on persistent liver infection. Regardless, we confirm prior results showing a solo cccDNA is sufficient to re-infect an entire liver, with corresponding concerns for transplantation and treatment.

Highlights

For the nearly 250 million people worldwide suffering from chronic hepatitis B virus (HBV) infection, there are few effective options for treatment [1] and its elimination is exceptionally difficult
Our focus on spatial distributions within the sinusoids of the liver is inspired by known gradients of, for instance, oxygen and nutrients [25] that may in turn affect intracellular HBV dynamics, the uptake of HBV via the NTCP, or immune-cell responses
We investigated the following spatial-heterogeneities within the sinusoid: (i) gradients of immune responses, active immune cell cytolytic removal of infected hepatocytes; (ii) gradients of HBV replication efficiency; (iii) gradients of NTCP uptake of HBV and combinations thereof

Summary

Introduction

For the nearly 250 million people worldwide suffering from chronic hepatitis B virus (HBV) infection, there are few effective options for treatment [1] and its elimination is exceptionally difficult. Primary infection is maternal-neonatal vertical, and 5% of horizontal or personto-person [2], resulting in entrenchment of closed circularly-covalent DNA (cccDNA). CccDNA persistence and HBV resurgence (e.g., during immunosuppression for chemotherapy [3]) is associated with liver pathologies such as tissue damage (fibrosis, cirrhosis) and hepatic carcinomas [4]. Current treatments are mitigatory and require sustained and prolonged.

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