ReviewThe Biology and Life-Cycle of Human Papillomaviruses
Section snippets
The diversity of human papillomaviruses and the diseases that they cause
To date, more than 150 human papillomavirus (HPV) types have been completely sequenced (Fig. 1), along with over 60 animal papillomaviruses (PV) (see Papillomavirus Episteme (PaVE); http://pave.niaid.nih.gov/#home) and [1]). The presence of PVs in mammals, as well as in various diverse hosts, including birds, turtles and snakes, suggests that they may be ubiquitously present amongst present day amniotes (i.e., mammals, birds and reptiles) [2].
Papillomavirus types found in humans are divided
High- and low-risk types and their association with cancers
The Alpha PVs are divided into cutaneous and mucosal types, and the mucosal types are further subdivided into high-risk and low-risk groups [1]. The cutaneous Alpha types are also ‘low-risk’, and include HPV2 and 57, which cause common warts, and HPV3 and 10, which cause flat warts [1], [20].
The low-risk mucosal types (Fig. 2A), which despite their name can also cause cutaneous genital lesions, share a low-risk HPV life-cycle organisation and do not typically cause neoplasia [29] (Figs. 4B and 5
The normal productive life-cycle of high- and low-risk papillomaviruses
Whether a productive life-cycle is or is not completed depends on the nature of the epithelial site where infection occurs, as well as on the presence of external factors such as hormones [58] and cytokines [59]. Experimental models suggest that infection requires access of virus particles (composed of viral DNA and two capsid proteins, L1 and L2, which form icosahedral capsid [60], [61]) to the basal lamina, and the interaction with heparin sulphate proteoglycans [62], [63], [64] and possibly
Life-cycle deregulation and cancer progression
The ordered expression of viral gene products that leads to virus particle production is disrupted in HPV-associated neoplasia (Figure 6, Figure 7). In cervical disease, where most research has been done, it is generally thought that the levels of E6 and E7 expression increase from cervical intraepithelial neoplasia grade 1 to 3 (CIN1 to CIN3), and that these changes in gene expression directly underlie the neoplastic phenotype. In this scheme, CIN1 lesions typically retain the ability to
Lesion regression, latency and clearance
Although high-risk HPV infection is common, with over 80% of women becoming infected at some stage in their life, cervical cancer arises only rarely as a result of infection. Most infections are cleared as a result of a cell-mediated immune response, and do not persist long enough for deregulated gene expression and the accumulation of secondary genetic errors to occur. HPV16 has an average length of persistence that is longer than most other high-risk types, and this may contribute to its
Conclusions
Human papillomaviruses have evolved over millions of years to survive in a wide range of animal species, including humans. As is typical of viruses that have co-evolved with their hosts, many PVs produce only chronic, inapparent infections, and produce virions from the surface of infected epithelium without apparent detriment to the host. This is the case for many Beta and Gamma HPV types. However, not all HPV types use the same strategy, and it appears that several of the Alpha PVs, in
Acknowledgements
The E4/MCM staining shown in Fig. 7A was produced by Heather Griffin (NIMR, London, UK) using a tissue section prepared as part of an ongoing collaboration with Robert Jach, Krzysztof Okoń and Grzegorz Dyduch at the Jagiellonian University Medical College, Krakow, Poland. The LCM images shown in Fig. 7B was produced by Rene Bax and David Jenkins at DDL, Voorburg, Holland. IG Bravo is partially supported by public grants from the disappeared Spanish Ministry for Science and Innovation
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