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

Abstract

For nearly 250 million people worldwide suffering from chronic hepatitis B virus (HBV) infection, there are few effective options for treatment (Schweitzer et al., 2015). Elimination of HBV from liver tissue remains an elusive goal; chronic HBV is exceptionally difficult to treat. It results mainly from maternal-neonatal vertical infection but also in roughly 5% of horizontal infections (Rehermann, 2013), and is characterized by the entrenchment of viral covalently closed circular DNA (cccDNA) in host nuclei. cccDNA persistence and HBV resurgence under multiple scenarios [e.g., immunosuppression for chemotherapy (Hoofnagle, 2009)] are associated with liver pathologies such as tissue damage (fibrosis, cirrhosis) and hepatic carcinomas (Ikeda et al., 2010). Current treatments are aimed at mitigating such long-term pathological effects and require sustained and prolonged protocols, yet do not eradicate cccDNA leading to reactivation upon cessation (Guo and Guo, 2015). cccDNA entrenchment further evades detection—with some occult DNA levels well under 100 copies/ml—complicating transfusions or transplantations (Schmeltzer and Sherman, 2010). Efforts at mimicking and exploiting the successful immune response in the 95% of acute horizontal infections requires delineating precisely how the immune systems interact with HBV, and we do not have a clear characterization of the HBV-immune dynamic (Guidotti et al., 2015; Seeger and Mason, 2015). The two levels of infectious response, (i) the innate and (ii) the adaptive, recognize and respond in distinct ways to HBV challenges while modulating each other. Their success or failure influences whether the HBV challenges are resolved with an acute infection and immunity, or a chronic condition with numerous collateral complications (Rehermann, 2013). Innate immune activity, as with the natural killer (NK) cells and resident liver macrophages, or the Kupffer cells, and its more generalized recognition of pathogens are proposed either essentially blind to a “stealth” infection of HBV (Chang and Guo, 2015), or are a critical and “exquisite” guardian against successful HBV colonization (Guidotti et al., 2015). Meanwhile, adaptive responses (e.g., CD4+/CD8+ T-Cells) and their specific targeting of HBV are proposed essential for restricting infection to the transient acute while buttressing immunity against future challenges (Chisari et al., 2010). Evaluating novel treatments is further complicated by observations of evidently disruptive interactions between innate and adaptive immune activity. Uptake mechanisms observed key to HBV invasion, the sodium-taurocholate co-transporting polypeptide or NTCP (Watashi et al., 2014), is a promising target for blocking HBV uptake. However, innate release of interleukin-6 (IL-6) that interferes with HBV replication and downregulates NTCP also blocks apoptotic mechanisms and may even assist HBV progress (Hosel et al., 2009). The HBV cccDNA itself is a natural prime target, and in vitro studies with HepaRG cell lines that show interferon-alpha and lymphotoxin-beta stimulus without cytolytic behavior appears promising (Lucifora et al., 2014), but must be advanced with caution. Innate NK cells were observed to perform unexpected termination of adaptive CD8+ T-cells when pharmacologically stimulated to produce interferon family cytokines (Guidotti et al., 2015). Additionally, dependence of chronic or acute manifestations on the sheer number of HBV suggests an optimal invasion population strategy for HBV (Asabe et al., 2009), presumably evading detection but sufficient for colonization. Unfortunately, direct study of the initial HBV-immune dynamic in patients is difficult or simply not possible, hence the attention given to animal and mathematical models (Murray and Goyal, 2015; Cangelosi et al., 2017).