Biochemical insights into the evolution of papillomaviral carcinogenesis

Abstract

Persistent infection with a subset of human papillomaviruses (HPVs) has been conclusively shown to be the cause of cervical cancer. Only a small subset of the ∼150 characterized HPVs has been shown to be oncogenic. Phylogenetic analyses cluster these oncogenic viruses (OTs) together. Therefore, cervical cancer can be viewed as an evolutionary trait of these viruses that was independently gained by and is conserved in these so-called High Risk (HR) viruses. However, not all PVs in this HR-clade are OTs.;The genetic basis of the oncogenic phenotype implies that the use of molecular evolution techniques should lead to an understanding of the involved (Darwinian) mechanisms. Since HPVs use the host cell's machinery to replicate their DNA, cell cycle progression in these terminally differentiated cells needs to be activated. It is likely that the oncogenic phenotype of a subset of viruses is the manifestation of 'collateral damage' of viral adaptation. Either this adapted phenotype is present only in the OTs, or the effects are stronger in these. In order to identify this viral phenotype, I combined epidemiological data (i.e., viral risk classification) with molecular phylogeny to guide the interpretation of biochemical assays. I have investigated specific phenotypes, which based on HPV16, were previously associated with oncogenic risk. Using representative HPVs covering the evolutionary spectrum of the Alphapapillomavirus (alpha-PV) genus, I tested the effects of these viruses on three previously described pathways. If my hypothesis concerning the evolutionary nature of oncogenesis is true, this approach will allow me to identify viral phenotypes and the underlying genetic determinants associated with cancer.;Using this approach I present data suggesting that while, degradation of PDZ proteins and activation of unlicensed cell cycle progression are likely associated with the viral requirement to use the host cells' machinery, up-regulation of the hTERT promoter is a phenotype uniquely associated with oncogenic viruses. This observation makes hTERT regulation the only currently described biochemical phenotype tightly associated with HPV carcinogenicity.