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

Quentin Cangelosi, Shawn A Means and Harvey Ho

PLOS ONE, 2017, vol. 12, issue 12, 1-28

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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0188209

DOI: 10.1371/journal.pone.0188209

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