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Completion of the viral life cycle is absolutely dependent on a process of keratinocyte differentiation. Theoretically, time from infection to release of infective virions can take as short as 3 weeks because within this time keratinocytes usually undergo complete differentiation and desquamate. In reality, this period can vary from weeks to months.
- Infection Viruses infect primitive basal keratinocytes presumably via tiny tears. Very low amount of viruses (multiplicity of infection, MOI) is sufficient. After the initial infection the viral DNA is delivered to the cell nucleus in complex with the L2 minor capsid protein.
- Viral replication
initiation At some time after infection there is an initial round of viral DNA replication. This process is highly dependent on presence of origin of replication and the levels of E1 and E2 proteins which expression is tightly regulated on transcriptional as well as translational levels. After viral copies number reached approx. 50-100 per cell, the cell is thought to enter next, proliferating stage, of its differentiation cycle.
replication The stage of episomal (extrachromosomal) viral replication. The viral genome is maintained in the dividing cells to sustain a persistent infection. The maintenance replication is coupled to that of the host cell and, on average, each genome is replicated once per cell cycle to give an overall constant and very low copy number (estimated to be less than 20 copies per cell). This process depends on the host's cell mitotic activity which supplies necessary enzymes for the viral replication such as DNA polymerases and other factors. The viral proteins E6 and E7 are expressed at this stage. By interfering with expression of p53 and retinoblastoma proteins, respectively, they delay the differentiation and prolong proliferation of the cells. At this stage integration of viral DNA into the host's genome might occur.
replication As soon as infected keratinocytes start to enter differentiation stage, the viral genomes are amplified to a high copy number (at least 1000 copies/cell) and are packaged in the capsids of infective virions. The viral proteins E6 and E7 are absolutely required for viral vegetative amplification in terminally differentiated cells because they inhibit apoptosis, induce S-phase like state and keep cellular DNA synthesis machinery available for the assembling viruses. Eventually, majority of the virus-laden keratinocytes cease to divide at the final stage of differentiation, desquamate during skin-to-skin or mucosa-to-mucosa contact and transmit viruses to another host. A small portion of the cells might keep dividing thus maintaining a chronic infection.