Balkan Journal of Medical Genetics

In the past decade, experimental studies on HPV 16 and HPV 18, the two viruses most frequently isolated from the genital tract, have led to an understanding of the means by which they transform and immortalize cells. Their role has been established by the regular presence of their DNA in tumor biopsies, the expression of viral oncogenes (E6 and E7) in those tumors, the determination of transforming properties of these oncogenes, the maintenance of the malignant phenotype by the continuous expression of these oncogenes and the interaction of viral oncoproteins with growth-regulating host-cell proteins.

The HR HPV E6 and E7 oncoproteins interact with cellular proteins that regulate cell-cycle progression. In particular, the E6 protein binds to p53, and the E7 protein binds to the retinoblastoma (Rb) gene product. Both, p53 and Rb are tumor suppressors that prevent cellular transformation by regulating cell division and proliferation. If either of these proteins is absent, mutated, or modified, cellular transformation occurs. High risk HPV E6 and E7 oncoproteins cause degradation of p53 and inactivation of Rb, respectively, thereby removing inhibitory pathways of cellular proliferation, and concomitantly, providing HPV-infected cells with a growth advantage [11].

The difference between LR and HR HPV types is mainly in the physical state of their genome, that of HR HPVs is frequently randomly integrated in host cell chromosomes. This contrasts with that of LR HPVs, that is extrachromosomal and replicates as an episome or plasmid. The integration of the HR HPV genome generally occurs within the E1 and E2 regions that encode viral regulatory proteins involved directly in the control of viral transcription, and DNA replication. The resulting disruption of the region leads to loss of function of these two genes and consequently to deregulation of the E6 and E7 genes. Uncontrolled and continued expression of E6 and E7 genes induces cell proliferation, transformation and finally immortalization. Furthermore, E6 and E7 proteins of HR HPVs bind more efficiently to p53 and Rb than those of LR HPVs, and the E6 protein of HR HPVs degrades p53 in contrast to that of LR HPV. Human papillomavirus-mediated cervical carcinogenesis is a multi-step process that may last up to about 15 years. The crucial events are persistent HR HPV infection and over expression of viral oncoproteins, and consequently, host-cell genetic instability including telomerase activation [12].