<br><br />Papillomaviruses and cancer<br />Papillomaviruses (PVs) are relatively small, non-enveloped viruses that consist of an icosahedral <a href='http://www.luteinizing-hormone-releasing-hormone-human-acetate-salt.com/viewtopic.php?f=2&t=6878
'>sphingosine kinase </a> that harbours a circular, double-stranded DNA genome. The capsid is composed of 72 major capsid protein L1 pentamers termed capsomeres, and a minimum of 12 minor capsid protein L2 monomers. The viral genome contains open reading frames (ORF) for early (E) regulatory (E1, E2 and E4) and up to three transforming proteins (E6, E7 and frequently E5), and for the late (L) capsid proteins L1 and L2. A non-coding long control region (LCR) is located between the L1 and E6 ORFs and is responsible for viral replication and transcription (Campo, 2006b). The productive life cycle of PVs is tightly linked to the differentiation of keratinocytes. De novo infection occurs via micro-abrasions which allow virions to gain access to basal keratinocytes presenting the necessary surface molecules for virion attachment and endocytosis (Giroglou et al., 2001; Day et al., 2003; Spoden et al., 2008). Following virion disassembly, the virus expresses its early regulatory and transforming genes in the basal and suprabasal epidermal layers (Doorbar, 2005). In the differentiated cells of the spinous and granular layer, the viral genome replicates by 10–100 times. The major L1 and the minor L2 capsid proteins are expressed in the granular and final squamous layers. The genomes are then packaged by directed assembly of L1 and L2 into virions which are shed via desquamation (Graham, 2006). PV infection is not always productive. The viral genome can be maintained in infected cells as multiple episomes that replicate in synchrony with the cell cycle (Chambers et al., 2003), or integrate into the host cell genome (Doorbar et al., 2012).<br />Early research in natural animal models has revealed that PVs are usually species-specific and have a pronounced tropism for specific cellular environments, i.e. cutaneous and/or mucosal keratinocytes. Bovine Delta-papillomavirus types 1, 2 and 13 are an exception to this rule in that they can also infect fibroblasts and other ungulate species in addition to cattle (Campo, 2006a; Lunardi et al., 2013).<br />Thus far, more than 160 human PV (HPV) types have been sequenced completely (De Villiers, 2013). From these, 15 types have been identified as carcinogenic in humans and are therefore termed high-risk HPVs (hrHPVs; Munoz et al., 2003; Parkin, 2006; De Martel et al., 2012; Forman et al., 2012). In contrast, only a limited number of equid PV types (1–7) are known to date (Scase et al., 2010; Lange et al., 2011, 2013b; Nasir and Brandt, 2013). Consequently, the aetiology of various potentially PV-induced cutaneous and mucosal cancers in equids remains to be established. In addition, there are currently no vaccines to protect horses from confirmed PV-induced tumours. In humans, it is currently accepted that infection by mucosal hrHPV types causes virtually all cervical cancers, most anal cancers, up to 50% of vulval, vaginal and penile cancers, and about 25% of head and neck SCCs (HNSCCs; Zur Hausen, 1996, 2000; Dayyani et al., 2010). E6 and E7 are the major viral oncoproteins driving HPV-induced carcinogenesis. Malignant transformation of persistently infected epidermal <a href='http://en.wikipedia.org/wiki/Cell_%28biology%29
'>cells</a> is achieved by complex interactions between these oncoproteins and cellular fa<img src="http://www.apexbt.com//media/diy/images/struct/B1405.png#
" />ctors involved in cell-cycle regulation (Feller et al., 2010a,b). Cytologically and histologically, hrHPV-induced human genital precancerous lesions and SCC each display characteristic features. Precancerous lesions mainly include warts (condylomas) and <img src="http://farm5.static.flickr.com/4394/36886907310_048ee309d9.jpg
" align="left" width="270" style="padding:10px;"/> intraepithelial neoplasia. Genital warts are usually benign exophytic lesions with koilocytosis, infected by low-risk (lr-), i.e. non-carcinogenic HPV types. However, some warts also show cytologic atypia, abnormal mitotic figures, contain intranuclear inclusion bodies and have the potential to progress to SCC. This subset of warts is hrHPV-induced and precancerous (Cubilla et al., 2016). HrHPV-associated penile intraepithelial lesions (PeIN) present as warty or basaloid neoplasms or, in case of warty-basaloid lesions, as a mixture of both, consisting of immature, atypical basaloid-type keratinocytes with intranuclear viral inclusion bodies, and a condylomatous surface (Stratton and Culkin, 2016). Interestingly, there is also emerging evidence for the existence of human penile plaques, i.e. hrHPV-positive flat whitish acanthotic lesions with mild koilocytosis, that could represent a link between penile warts and PeIN (Cubilla et al., 2004, 2016). Similarly, penile plaques have been recognised as SCC precursor lesions in horses (Scott and Miller, 2003; Van den Top et al., 2008b; Knottenbelt, 2009; Scase et al., 2010). Like human penile precancerous warts, equine genital papillomas show acanthosis and koilocytes and contain intranuclear bodies consistent with viral inclusions. Equine genital SCCs closely resemble their human hrHPV-associated counterpart in that they comprise hyperproliferative neoplastic keratinocytes of basaloid type that invade the subepithelial stroma. In combination, these findings suggest that equine genital SCC and precursor lesions, i.e. plaques, papillomas and CIS, are also induced by PVs (Scott and Miller, 2003; Cubilla et al., 2004; Scase et al., 2010; Chaux et al., 2012a,b; Velazquez et al., 2012).