Mechanism of neoplastic development

 

The highest risk of cancer development occurs after prolonged persistent infection. The virus establishes the persistent infection at maintenance replication stage by obviating host's immune responses and, ultimately, integrating its DNA into the host's genome.

In natural genital HPV infection, lesions are cleared as a result of a successful cell-mediated immune response directed against early (E1 and E2) HPV proteins. Also, the humoral (mediated by antibodies in the blood) immune response might be induced against late HPV proteins, specifically, against capsid proteins L1 and L2. The latter reaction is usually quite weak because free virus particles are shed from the surface of squamous epithelia with poor access to blood and lymphatic vessels where immune responses are initiated, furthermore, because the virions are accumulated in cells destined for death by natural causes, there is no viral-induced cytolysis or necrosis and, therefore no inflammation.

As it was mentioned before, the viral oncogenes E6 and E7, working in tandem, prolong proliferation (cell division) of cells by interfering with their differentiation program. By-product of this role in high-risk HPV infections is the deregulation of growth control in the infected cells that leads to development of neoplasia and, ultimately, invasive cancer. Expression of E6 and E7 proteins is tightly controlled by E2 protein, which is responsible for the viral replication and assembly. At some point of persistent episomal (extrachromosomal) viral replication, the integration of the viral genome into the host's genome might occur. The integration usually causes deletion or disruption of E2 while retaining a variable segment, including the E6 and E7 oncogenes and the LCR. Resulting sharp down-regulation of E2 expression in affected cells leads to overexpression of E6 and E7. The cells acquire a strong growth advantage and undergo clonal expansion manifested in neoplastic lesions. In addition, these cells also show genomic instability that further increases the risk of malignant transformation and immortalization of the affected cell lineages. Complete clearance of the residual viral episomes is considered a key step in HPV-related carcinogenesis because it results in full deregulation of expression of the oncogenes.
Interestingly, interferon response is a powerful systemic defense reaction of organism against invasion of viruses. Induction of the interferon during the phase of HPV infection when the integration events took place but some episomes are still present can lead to quick clearance of the persisting episomes and launch unbridled carcinogenesis.