P38: The effect of ‘re‐cycling’ genome DNA of HBV for the intracellular replication dynamics

Abstract

Hepatitis B virus (HBV) is a major causative agent of the acute and chronic hepatitis. The viral load observed in the peripheral blood is quite different between the acute and chronic hepatitis. The replication dynamics of HBV plays a critical role determining the clinical course of the hepatitis. We constructed a mathematical model for the replication process of HBV in infected cell to investigate the intracellular replication dynamics of HBV. The amount of newly produced virion is drastically changed by the slight alteration of the expression rate of viral genes, 3.5 kb RNA that contributes to the replication of the core particle and 2.1 kb RNA that is translated into HBs antigen. This model is based on the single cycle of HBV replication because the re-cycling of the genome in the newly replicated core particle is not taken into consideration. A part of the newly replicated HBV genome in the core particle should participate in further replication of HBV. On the other hand, a part of the core particle is packaged by the envelope to produce new virions those are released through the exocytosis of the host to expand the infection. Here we present the expanded model including the 're-cycling' process of the genome DNA of HBV. The model reveals that the HBV virion is exponentially reproduced through the positive feedback in the replication cycle under a certain condition. The result that the HBV can exponentially replicate when the expression of pre-genome RNA of HBV substantially exceeds that of 2.1 kb RNA is consistent with the result obtained from our previous model. To address the recycling process of HBV genome, more complicated replication dynamics of HBV can be described by our new model. In this study, we further investigate the effect of the reentry rate of HBV genome into the replication cycle for the virion production. When the re-entry rate becomes large the positive feedback can function to exponentially produce virion. When the re-entry rate becomes too large, the virion production is delayed the core particle becomes starved to produce the virion in the early phase of the infection. The trade-off between the initial speed and the final amount of HBV production plays a critical role in determining the optimal re-entry rate of HBV genome. There is an optimal re-entry rate to maximize the virion production of HBV. I would like to discuss the experimental and clinical implications of this optimal re-entry rate of HBV genome.