So far three models have been suggested to explain how transient hepadnavirus infections are cleared from the liver.
The cure model
The cccDNA pool clearance occurs mainly through cytokines while cell death and cell proliferation do not contribute significantly. Guidotti and colleagues demonstrate that at least 90% of the viral DNA was eliminated from the liver during a typical HBV infection by non-cytolytic processes that precede and are independent of the immune elimination of infected hepatocytes. They did not however determine if the viral cccDNA was susceptible to nonc-ytolytic control (Guidotti et al. 1999) Rating=1.
The death and compensatory model
In this model, cytokines suppress virus replication and renewal of cccDNA but do not have any effect on preexisting cccDNA that is eliminated by both cell death and mitotic loss. Virus clearance in this model could be achieved with about 0.7 liver equivalents of cumulative hepatocyte turnover (Mason et al. 2009) Review. A mathematical simulation in infected chimpanzees supports as well the notion that both non-cytopathic and cytopathic mechanisms could contribute to inhibit viral replication and strongly decrease cccDNA half-life (Murray et al. 2005) Rating=1.
The cell death model
In model 3, cccDNA loss occurs only via hepatocyte death. cccDNA is proposed to survive mitosis and to be distributed in a binomial fashion to progeny hepatocytes. Repeated mitosis in response to destruction of other infected hepatocytes eventually results in the formation of lineages of uninfected hepatocytes. Starting with an average of 30 copies of cccDNA per hepatocyte, this model would require about 2.6 liver equivalents of hepatocyte death to achieve virus clearance.
The minichromosome is very stable within the nucleus, and direct degradation within the infected cell of the cccDNA has never been reported. However, it is unclear how and to what extend the cccDNA localizes to new host nucleus after mitosis. In Epstein-Barr virus infection, EBNA1 maintains circular genomes in proliferating cells by tethering them to host chromosomes (Sears et al. 2004) Rating=2.