A compartmentalization model of hepatitis C virus replication: an appropriate distribution of HCV RNA for the effective replication.

Hepatitis C virus (HCV) infection is a major cause of liver disease. Ten to twenty percent of chronic hepatitis C will develop complications of chronic liver diseases such as liver cirrhosis and hepatocellular carcinoma. The culture system of HCV is established by the specific combination between HCV strain and a host cell. Some chimeras substituting core to NS2 into the analogous region of JFH1 strain fail to effectively replicate. Core to NS2 of HCV gene mainly encodes the structural protein of HCV virion and contributes to the virion assembly, while other regions mainly contribute to the genome replication. The balance between the virion assembly and the genome replication of chimera may differ from that of reference strain. We construct a mathematical model of the whole replication process of HCV in single infected cell. It is revealed by this model that there are two replication patterns of HCV, explosive and arrested replication. In the explosive replication, HCV can continue to exponentially reproduce its progeny. The explosive replication is caused by the effect of the positive feedback in the replication cycle. On the other hand, in the arrested replication, the replication is stalled after sufficiently long time has passed from the infection because of the depletion of the genome RNA of HCV. To avoid the arrest of replication, HCV RNA must be appropriately distributed to three distinct functions as a template for the genome replication, as a template for the translation of viral proteins and as a component of the viral particle. When the genome replication and the translation of viral proteins precede to the virion assembly, HCV can effectively replicate by explosive replication. It is suggested that some chimeras of HCV fail to effectively replicate because of the inappropriate distribution of HCV RNA to these functions.