Fig. 4.

Human Papillomavirus Regulation and De-regulation over the Human Lifespan. Extrapolation of our current concepts of papillomavirus infection and immune control to infection by high-risk HPV types over the human lifespan can explains current clinical observations. A(i) Initial infection and disease formation occurs in early adulthood, followed by immune resolution leading to ‘clearance’ or ‘apparent clearance’. Recurrence of the initial infection to levels where DNA levels rise above the clinical detection threshold does not occur in this case and the individual remains HPV-negative. New detection is the result of new infection. A(ii) Initial infection and disease formation occurs in early adulthood, but immune control suppresses viral gene expression without driving clearance of infection. HPV DNA levels rise above the clinical detection threshold sporadically throughout life. New HPV detection may result from reactivation of an existing controlled infection or the acquisition of a new infection. A(iii) The outcomes described in A(i) and (ii) may occur, but one HPV type persists as an active persistent infection with deregulated viral gene expression. At some epithelial sites, such as the cervical transformation zone or the tonsillar crypts, HSIL may not necessarily be preceded by LSIL, which will shorten the cancer progression time. B) Approximate timeframe of key events in the high risk HPV infectious cycle over the human life span. The different outcomes of immune regression are outlined in the ‘disease status’ row, with subclinical asymptomatic infection highlighted in red. Lifespan events such as pregnancy, stress, other illnesses and immune senescence during aging are known or anticipated to affect ability to detect HPV DNA. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)