Modeling reveals no direct role of the extent of HBV DNA integrations on the outcome of infection.

Hepatitis B virus (HBV) with its high prevalence and death toll is one of the most important infectious diseases to study. Yet, there is very little progress in the development of within-host models for HBV, which has subsequently hindered our understanding of this virus. The uncertainty around the proliferation of infected hepatocytes has been studied but never in association with other important biological continuous events such as integrations and superinfections. This is despite the fact that these processes affect the diversity and composition of infected cell population in the liver and an improved understanding of the cellular composition will undoubtedly assist in strategizing against this viral infection. Here, we developed novel mathematical models that incorporate these key biological processes and analyzed them both analytically and numerically. Unaffected by the extent of integrated DNA (IDNA), the outcome of HBV infection was primarily dictated by the balance between processes generating and killing infected hepatocytes containing covalent closed circular DNA (cccDNA). The superinfection was found to be a key process in the spread of HBV infection as its exclusion could not reproduce experimentally observed composition of infected hepatocytes at peak of acute HBV infection, a stage where our model predicts that infected hepatocytes most likely carry both cccDNA and IDNA. Our analysis further suggested the existence of some form of selective advantage of infected hepatocytes containing only IDNA to explain the viral dynamics observed during antiviral treatment and the transition from peak to acute infection. Finally, the fine line between liver destruction and resolution of acute HBV infection was found to be highly influenced by the fate of cccDNA during cellular proliferation.