Let sleeping dogs lie- unleashing the transforming power of dormant HPV

Abstract

The rate of infection with human papillomavirus (HPV) worldwide is about 80% of the adult population. Anogenital HPV infections are usually transient and cause no lasting damage. In about 15-20% of the cases, however, the HPV infection may persist and in about 1% it may cause transformation of the infected epithelium that might subsequently progress to overt cervical cancer. The hallmark of the malignant transformation is the integration of the viral genome into the host cell genome, resulting in upregulation of the transcription of the viral oncoproteins E6 and E7. The latter are expressed early in the course of the infection, interacting with the major regulators of the cell cycle progression so as to retain the host cell in a state favourable for the replication of the viral genome. Among the crucial cellular partners in the neoplastic transformation of HPV-infected cells are tumour-suppressor proteins such as p53 and pRb, products of protooncogenes such as p21/WAF1, chromatin structure modifiers such as HMGA1, and controllers of the cellular senescence such as the telomerase complex. The high-risk types of HPV seem to have developed mechanisms capable of evading or disabling virtually any defence. Nature has put in place against cancerous transformation, which could account for the high incidence of cervical dysplasia and cervical cancer despite the efforts the modern medicine and healthcare puts into screening programmes, prevention and therapy. The role of the deregulation of the expression of each of these groups of participants in the pathogenesis of activation of persistent dormant infection is reviewed and their impact on the risk for progression to higher grades of cervical intraepithelial neoplasia (CIN) and development of cervical cancer is assessed.