Summary: Human papillomaviruses (HPVs) have evolved over millions of years to propagate themselves in a range of different animal species including humans. Viruses that have co‐evolved slowly in this way typically cause chronic inapparent infections, with virion production in the absence of apparent disease. This is the case for many Beta and Gamma HPV types. The Alpha papillomavirus types have however evolved immunoevasion strategies that allow them to cause persistent visible papillomas. These viruses activate the cell cycle as the infected epithelial cell differentiates in order to create a replication competent environment that allows viral genome amplification and packaging into infectious particles. This is mediated by the viral E6, E7, and E5 proteins. High‐risk E6 and E7 proteins differ from their low‐risk counterparts however in being able to drive cell cycle entry in the upper epithelial layers and also to stimulate cell proliferation in the basal and parabasal layers. Deregulated expression of these cell cycle regulators underlies neoplasia and the eventual progression to cancer in individuals who cannot resolve high‐risk HPV infection. Most work to date has focused on the study of high‐risk HPV types such as HPV 16 and 18, which has led to an understanding of the molecular pathways subverted by these viruses. Such approaches will lead to the development of better strategies for disease treatment, including targeted antivirals and immunotherapeutics. Priorities are now focused toward understanding HPV neoplasias at sites other than the cervix (e.g. tonsils, other transformation zones) and toward understanding the mechanisms by which low‐risk HPV types can sometimes give rise to papillomatosis and under certain situations even cancers. Copyright © 2015 John Wiley & Sons, Ltd.

Papillomaviruses have evolved over many millions of years to propagate themselves at specific epithelial niches in a range of different host species. This has led to the great diversity of papillomaviruses that now exist, and to the appearance of distinct strategies for epithelial persistence. Many papillomaviruses minimise the risk of immune clearance by causing chronic asymptomatic infections, accompanied by long-term virion-production with only limited viral gene expression. Such lesions are typical of those caused by Beta HPV types in the general population, with viral activity being suppressed by host immunity. A second strategy requires the evolution of sophisticated immune evasion mechanisms, and allows some HPV types to cause prominent and persistent papillomas, even in immune competent individuals. Some Alphapapillomavirus types have evolved this strategy, including those that cause genital warts in young adults or common warts in children. These strategies reflect broad differences in virus protein function as well as differences in patterns of viral gene expression, with genotype-specific associations underlying the recent introduction of DNA testing, and also the introduction of vaccines to protect against cervical cancer. Interestingly, it appears that cellular environment and the site of infection affect viral pathogenicity by modulating viral gene expression. With the high-risk HPV gene products, changes in E6 and E7 expression are thought to account for the development of neoplasias at the endocervix, the anal and cervical transformation zones, and the tonsilar crypts and other oropharyngeal sites. A detailed analysis of site-specific patterns of gene expression and gene function is now prompted.

Human Papillomavirus (HPV) research has been dominated by the study of a subset of Alpha papillomaviruses that together cause almost 5% of human cancers worldwide, with the focus being on the two most prominent of these (HPV16 and 18). These viruses are referred to as 'high-risk' (hrHPV), to distinguish them from the over 200 prevalent HPV types that more commonly cause only benign epithelial lesions. The 'low-risk' (lrHPV) term used to describe this group belies their cumulative morbidity. Persistent laryngeal papillomas, which occur rarely in children and adults, require regular surgical de-bulking to allow breathing. Such infections are not curable, and despite being caused by HPV11 (a lrHPV) are associated with 1-3% risk of cancer progression if not resolved. Similarly, the ubiquitous Beta HPV types, which commonly cause asymptomatic infections at cutaneous sites, can sometimes cause debilitating papillomatosis with associated cancer risk. Recalcitrant genital warts, which affect 1 in 200 young adults in the general population, and even the ubiquitous common warts and verrucas that most of us at some time experience, cannot be reliably eradicated, with treatment strategies advancing little over the last 100 years. The review highlights molecular similarities between high and low-risk HPV types, and focuses on the different pathways that the two groups use to ensure persistent infection and adequate virus shedding from the epithelial surface. Understanding the normal patterns of viral gene expression that underlie lesion formation, and which also prevent loss of the infected basal cells in established lesions, are particularly important when considering new treatment options. Finally, the common requirement for deregulated viral gene expression and genome persistence in development of cancers, unites both high and low-risk HPV types, and when considered alongside viral protein functions, provides us with a working understanding of the mechanisms that underlie HPV-associated pathology.

Human papillomaviruses (HPV) cause cancer at a number of vulnerable epithelial sites, including the cervix, the anus and the oropharynx, with cervical cancer being the most significant in terms of numbers. The cervix has a complex epithelial organisation, and comprises the stratified epithelium of the ectocervix, the columnar epithelium of the endocervix, and the cervical transformation zone (TZ). Most cervical cancers arise at the TZ, which is a site where a stratified squamous epithelium can develop via metaplasia from a simple columnar epithelium. It is thought that this process is mediated by the cervical reserve cell, a specialised type of stem cell that is located at the TZ, which has been proposed as the target cell for HPV infection. Reserve cells may be derived from the basal cells of the ectocervix, or may originate from the cuboidal cells found at the squamo columnar junction. It appears that HPV infection of these diverse cell types, including the columnar cells of the endocervix, facilitates deregulated viral gene expression and the development of neoplasia, with different epithelial sites having different cancer risk. It is envisaged that these concepts may explain the vulnerability of the oropharynx, and other TZ regions where HPV-associated cancers arise.