Rasmirani and colleagues recently wrote a comprehensive review article about HPV-mediated neoplastic progression. According to them among 40 out of 184 HPVs with different genotype can transmit infectious disease. They are classified into low-risk, intermediate-risk and high-risk viruses. HPV16 and 18 have been found so far to be the most potent carcinogenic viruses.
Infection is a several step process starting with virus entry into host tissue and cells. First, HPV makes its entry into the tissue consisting of several layers of cervical epithelial cells through micro-wounds or micro-abresions. On the surface of the epithelial cells the virus finds specific receptors and co-receptors to bind to. As a next step the virus is pirating internalization processes that the cell is normally using for uptake of important molecules to maintain itself. These internalization processes are called clathrin-dependent or cavelolae-mediated endocytosis and are quite complex and well evolved biologic mechanisms of internalization.
Once inside the cell, the virus enters the nucleus through breaks in the nuclear envelope where it replicates first its early genes (E1, E2, E3, E4, E5 and E6) regulating vegetative and productive phases of the viral life cycle and then late genes (L1 and L2) encoding capsid proteins. That’s how the virus amplifies and assembles into new viral particles to be transmitted into neighboring cells repeating the same steps over and over again until the host’s immune system detects and stops it …. Or not …..
DNA originating from high-risk HPV is often integrated into the human genome for example at integration hotspots in various regions where DNA double strand breaks are failed to be repaired. DNA damage can happen through environmental factors inducing oxidation as well as HPV proteins E1, E6 and E7. These viral proteins targeting a process called DNA damage response (DDR) in various ways for example by disturbing cell cycle checkpoint regulators. During the process of integration one consequence is the overexpression of E6 and E7 resulting in an increased deregulation of the cell cycle and a growth advantage of more and more epithelial cells of the cervical tissues. This can lead to tumor formation and carcinogenesis.
Over time a snowball effect occurs resulting in disturbance of tissue integrity and increasing genomic instability including a number of genes that are known to be amplified and/or mutated in different types of tumors such as MYC, ERBB2 and other genes.
The above description is highly simplified and there are other mechanisms that high-risk HPVs are able to use during disease progression such as inflammation, oxidation and epigenetic modification. I will not elaborate on them in this posting. I am writing this to motivate women and men to get vaccinated and screened on a regular basis so that hopefully one day HPV-caused cancers are part of the group called RARE diseases.
Senapati, R. et al. (2016) Molecular mechanisms of HPV mediated neoplastic progression. Infectious Agents and Cancer. 11: 59.