The intracellular dynamics of hepatitis B virus (HBV) replication with reproduced virion “re-cycling”

Abstract

Hepatitis B virus (HBV) is a causative agent of hepatitis. Clinical outcome of hepatitis type B depends on the viral titer observed in the peripheral blood of the patient. In the chronic hepatitis patient, production of HBV virion remains low level. On the other hand, the viral load prominently increases in fulminant hepatitis patient as compared with that in the chronic hepatitis patient. We previously proposed a mathematical model describing the intracellular dynamics of HBV replication. Our model clarified that there are two distinguishable replication patterns of HBV named “arrested” and “explosive” replication. In the arrested replication, the amount of virion newly reproduced from an infected cell remains low level, while the amount of virion extremely increases in the explosive replication. Viral load is drastically changed by slight alteration of expression ratio of 3.5kb RNA to 2.4kb mRNA of HBV. Though our model provided the switching mechanism determining the replication pattern of HBV, HBV dynamics is determined by not only the expression pattern of viral genes. In this study, “recycling” of HBV virion in the replication cycle is investigated as a new factor affecting the intracellular dynamics of HBV replication. A part of newly produced virion of HBV is reused as a core particle that is a resource of HBV replication. This recycling of HBV virion lowers the threshold for the explosive replication when waiting time for the next cycle of the replication is large. It is seemingly contradicting that prominent production of HBV is caused by large recycling rate and small release rate of HBV virion from infected cell to extracellular space. But the recycling of HBV virion can contribute to the positive feedback cycle of HBV replication for the explosive replication to accumulate the core particle as a resource of HBV replication in an infected cell. Accumulation of core particle in the infected cell can be risk factor for the exacerbation of hepatitis rather than rapid release of HBV virion from the infected cell.