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Literature on Cervical Cancer

Human papillomavirus molecular biology and disease association

John Doorbar *, Nagayasu Egawa, et. Al.,

Rev. Med. Virol. 2015; 25: 2–23. 25 June 2014

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 per- sistent visible papillomas. These viruses activate the cell cycle as the infected epithelial cell differentiates in order to cre- ate 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 counter- parts 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 fo- cused 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.
Received: 25 March 2014; Revised: 12 June 2014; Accepted: 25 June 2014

     Papillomaviruses comprise a diverse group of vi- ruses that infect both humans and animals. Their origin appears linked to changes in the epithelium of their ancestral host as the first reptiles emerged around 350 million years ago. Since then, they have co-evolved with their respective hosts, with little cross-transfer between species, and are now found in birds, reptiles, marsupials, and mammals, but not in amphibians or lower phylogenetic orders (Figure 1A) [1]. Viruses that slowly evolve with their hosts in this way typically cause chronic inap- parent infections, rather than serious disease [2]. This is the case for many if not most papillomavi- ruses, and indeed, HPVs can be isolated from skin swabs and plucked hairs from normal immuno- competent individuals in the general population [3,4]. As a result of such observations, it is thought that many HPVs may in fact persist in the popula- tion as commensals rather than being associated with obvious disease pathology [4,5].
    The study of HPVs has been driven not by these widespread inapparent infections, but by the severity to which some HPV-associated diseases can progress. Most significant of these is cervical cancer, which can result from persistent infection with a group of “high-risk” HPVs [6–8]. The low- risk HPV types, although not usually associated with cancer development, can cause problematic and debilitating disease in some individuals. The association of HPV type 11 with RRP is a key

*Correspondence to: J. Doorbar, Department of Pathology, University of Cambridge,   Tennis Court Road, Cambridge, CB2 1QP, UK.
All authors contributed equally to the content of the review and are listed alphabetically.

Abbreviations used BCC, basal cell carcinoma; BD, Bowen’s disease; cAMP, cyclic AMP; CIN, cervical intraepithelial neoplasia; CR1, conserved region 1; CR2,
conserved region 2; E, early (viral genome); HN, head and neck; HPV, human papillomavirus; L, late (viral genome); LCR, long control region; LSIL, low-grade squamous intraepithelial lesion; PAE, polyadenylation early; PAL, polyadenylation late; PBM, PDZ binding motif; RRP,
recurrent respiratory papillomatosis; SCC, squamous cell carcinomas.

Figure 1. (A) Evolutionary tree showing the proposed appearance of an ancestral “papillomavirus” between the branch point leading to amphibians and reptiles. It is thought that virus/host co-evolution has occurred during speciation, and that this has led to the widespread distribution of papillomaviruses in organisms as diverse as snakes, birds, and mammals, (B) The human papillomaviruses types found in humans fall into five genera, with the Alpha and the Beta/Gamma genera representing the largest groups. Human papillomaviruses types from the Alpha genus are often classified as low-risk cutaneous (gray), low-risk mucosal (orange), or high-risk (pink). The high-risk types identified using red text are confirmed as “human carcinogens” on the basis of epidemiological data. The remaining high-risk types are “probable” or “possible” carcinogens. The evolutionary tree is based on alignment of the E1, E2, L1, and L2 genes [6], (C) Percentage of cervical cancers that are causally attributed to infection with members of the Alpha genus. Members of the Alpha 9 and 7 species have been studied most thoroughly