Transboundary and Emerging Diseases

REVIEW ARTICLE

Bovine Papillomavirus: New Insights into an Old Disease F. Bocaneti1,*, G. Altamura2,*, A. Corteggio2, E. Velescu1, F. Roperto2 and G. Borzacchiello2 1 2

Department of Public Health, Faculty of Veterinary Medicine, University of Agriculture Sciences and Veterinary Medicine, Iasi, Romania Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Napoli, Italy

Keywords: bovine papillomavirus; E5; viral oncology Correspondence: G. Borzacchiello. Department of Veterinary Medicine and Animal Productions, Via F. Delpino, 1, 80137 – Napoli, Italy. Tel.: 0039 081 2536467; Fax: 0039 081 2536186; E-mail: [email protected] *These two authors contributed equally to the work.

Received for publication September 18, 2013

Summary Bovine papillomaviruses (BPVs) are small DNA tumoral viruses able to induce benign cutaneous and/or mucosal epithelial lesions. Generally, the benign tumours affecting the skin or mucosa spontaneously regress, but under special circumstances, the defence system may be overwhelmed, thus leading to cancer, especially in the presence of immunosuppressant and mutagen agents from bracken fern. To date, thirteen different BPV genotypes have been associated with skin and mucosal tumours in cattle, and out of these, only four types (BPV-1, -2, -5 and -13) cross-infect other species. Recent investigations in vivo have revealed new insights into the epidemiology and pathogenesis of this viral infection. This review briefly discusses viral epidemiology, will give data on BPV genome structure and viral genes and will describe the cellular events and new aspects of both cutaneous and mucosal tumours in large ruminants. Finally, some aspects of active immunization will be described.

doi:10.1111/tbed.12222

Introduction The breeding of large ruminants is being challenged by various skin and/or mucosal disorders that maybe the cause of significant economic losses on the part of breeders (e.g. skin quality depreciation, slow growth of the animals, loss of weight and decrease in milk production). In addition to this important aspect of veterinary interest, the importance of bovine papillomaviruses (BPVs) lies in the fact that it has represented one of the most extensively studied animal models of viral carcinogenesis. Although the vast majority of the experimental systems have studied the cell transformation induced by human papillomaviruses (HPVs) in vitro, the first observations concerning the cellular mechanisms during papillomavirusinduced cell transformation were provided by studies on BPV-1 (Campo, 1992). BPV-1 DNA has the unusual ability to morphologically transform and replicates in mouse cells in culture. This property has meant that BPV has become one of the most extensively studied animal papillomavirus (PV)-based models useful in understanding the oncogenic potential of the virus (Lowy et al., 1980). © 2014 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.

Studies of the BPV viral mechanisms and cell transformations have provided invaluable insights into many aspects of this infection. This review focuses on the biological features of BPV infections in large ruminants and highlights new, unknown aspects of this viral infection. BPV: Generalities, Heterogeneity, Epidemiology and Geographical Distribution Bovine papillomaviruses belong to the Papillomaviridae family, which consists of a large number of small DNA oncogenic viruses infecting the epithelium and mucosa of many animals as well as humans causing benign hyperproliferative lesions or cancers. Based on their L1 nucleotide sequence alignment and biological and medical properties, PVs have been divided into 29 genera (Bernard et al., 2010). Following the criteria mentioned above, thirteen BPV genotypes have been characterized so far and classified into three genera: Deltapapillomaviruses (BPV-1, -2, -13) inducing cutaneous fibropapillomas which consist of both epithelial and dermal components (Nasir and Campo, 1

Bovine Papillomavirus

2008; Lunardi et al., 2012), Xipapillomaviruses (BPV-3, -4, -6, -9, -10, -11, -12; Hatama et al., 2008, 2011) responsible for the occurrence of true papillomas, strictly epitheliotropic and Epsilonpapillomaviruses (BPV-5, -8) inducing both true papillomas and fibropapillomas (Tomita et al., 2007a) and an as yet unassigned PV genus (BPV-7; Ogawa et al., 2007). This classification cannot be considered definitive since Batista et al. (2013) reported very recently a more frequent occurrence of co-infections and a possible association of pure epitheliotropic types with cutaneous fibropapillomas. Additionally, as a general rule, PVs are species specific, but the exception to this rule is BPV-1, -2 and recently -5 and -13, which can jump the species barrier infecting buffaloes, equines, yaks, tapirs, giraffes, donkeys, bisons and zebras (Lohr et al., 2005; Literak et al., 2006; Kidney and Berrocal, 2008; Nasir and Campo, 2008; Silvestre et al., 2009; Pangty et al., 2010; van Dyk et al., 2011; Bam et al., 2012; Kumar et al., 2013; Lunardi et al., 2013). Bovine papillomaviruses infect large ruminants worldwide. A great number of cases are recorded in regions with a great density of these species (Italy, United Kingdom, Germany, Japan, India, United States of America and Brazil; Campo and Jarrett, 1986; Campo, 1995; Ogawa et al., 2004; Singh et al., 2009; Schmitt et al., 2010; Carvalho et al., 2012). In Italy, Borzacchiello et al. detected the BPV-2 in bovine urinary bladder tumours and BPV-1 in equine sarcoids (Borzacchiello et al., 2003a; Borzacchiello and Corteggio, 2009). Furthermore, Roperto et al., (2012) identified BPV-1/-2 DNA in the placenta of pregnant cows suffering from chronic enzootic haematuria (CEH), while Silvestre et al. (2009) demonstrated that BPV-1 infection in the water buffalo is associated with cutaneous, perivulvar and vulvar fibropapilloma. In Scotland, due to the endemic spread of bracken fern, BPV was reported to be co-involved in the occurrence of cancers of the alimentary canal and urinary bladder in cattle (Campo et al., 1985). In India, recent studies conducted on cutaneous warts in cattle revealed that the DNA of BPV-1 and -2 is present in both normal skin and cutaneous warts, while in buffaloes, the tested samples showed either single or mixed infections, confirming the high prevalence of the infection in these two species (Pangty et al., 2010). Recently, BPV-2 DNA has been detected in urine and urinary bladder lesions in cows in a CEH endemic region of India (Pathania et al., 2012). The presence of BPV-5 along with BPV-1 and -2 has been reported in ruminal wart-like lesions of buffalo, strengthening the widespread of these virus types and their ability to jump the species (Kumar et al., 2013). Viral transmission occurs through direct contact with an infected tissue, contaminated surfaces or objects and 2

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requires the infection of basal cells of the epithelium through micro-abrasions or wounds (Jarrett, 1985a). Virus entry may result in an asymptomatic, latent infection (McBride, 2008). Moreover, it has been demonstrated that BPV-1 DNA maybe transmitted by different species of flies, including both biting and non-biting species (Finlay et al., 2009). New insights into viral transmission were also revealed by the detection of BPV1/-2/-4 in asymptomatic and papillomatosis-affected animals in non-epithelial tissues and fluids, such as blood, lymphocytes, seminal fluid, spermatozoa, milk, urine, oocytes, ovary, uterus, cumulus cells and uterine lavage, which are all considered as reservoirs of viral infection (Stocco dos Santos et al., 1998; Roperto et al., 2008; Diniz et al., 2009; Lindsey et al., 2009; Silva et al., 2013b). Recently, besides horizontal transmission, vertical transmission has also been reported. BPV DNA has been detected both in bovine uterus, amniotic fluid and placenta and in blood samples collected from offspring, suggesting a potential role of BPV in vertical transmission via blood cells present in reproductive tissues or directly by reproductive cells (Yaguiu et al., 2008). Moreover, Roperto et al. (2012) showed that the placenta of pregnant cows suffering from urinary bladder tumours may be a site of BPV-2 productive infection (Roperto et al., 2012), thereby strengthening the hypothesis of vertical transmission. In humans, the existence of possible vertical transmission from the HPV-infected women and with epidermodysplasia verruciformis to the foetus has been suggested to occur through the following mechanisms: periconceptual, during pregnancy and during or immediately after birth (Favre et al., 1998; Rombaldi et al., 2008; Freitas et al., 2013). Regarding the maternal-to-foetal transmission of HPV, much controversy still exists, specifically about the magnitude of the risk and the route and timing of such vertical transmission (Lee et al., 2013). However, it has been suggested that the absence of persistent infection in infants at 6 months after delivery may suggest temporary inoculation rather than true vertical infection (Park et al., 2012). All these recently acquired data open a new interesting scenario regarding the ways the virus may spread and bring to light some previously unknown aspects of pathogenetic mechanisms. Recently, epidemiological studies in Brazil have detected BPV co-infections of all different genotypes on the same animal and lesion (Table 1), and a putative new BPV-11 subtype has been described (Carvalho et al., 2012). These observations shed light on BPV diversity, raising questions about the pathogenic roles played by the different genotypes (Silva et al., 2010; Batista et al., 2013). The species susceptible to BPV infection have recently been extended by the detection of BPV-1 and BPV-2 or © 2014 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.

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Table 1. Distribution of different bovine papillomaviruses (BPVs) genotypes associated with neoplastic disease. + and absence of co-infections

indicate the presence or the

BPV types

Bovine cutaneous fibropapillomas

Bovine gastrointestinal fibropapillomas

Bovine urinary bladder tumours

Buffalo fibropapillomas

BPV-1

Yes Co-infection+ Yes Co-infection+ Yes Co-infection+ Yes Co-infection+ Yes Co-infection+ Yes Co-infection+ No Co-infection Yes Co-infection+ Yes Co-infection+ Yes Co-infection+ Yes Co-infection+ No Co-infection Yes Co-infection

No Co-infection Yes Co-infection No Co-infection Yes Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection Yes Co-infection No Co-infection

Yes Co-infection Yes Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection

Yes Co-infection+ Yes Co-infection+ No Co-infection No Co-infection Yes Co-infection+ No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection No Co-infection

BPV-2 BPV-3 BPV-4 BPV-5 BPV-6 BPV-7 BPV-8 BPV-9 BPV-10 BPV- 11 BPV-12 BPV-13

their mixed infection in spontaneous cutaneous fibropapillomatosis in yaks (Bam et al., 2012). Interestingly, similar BPV-1/-2-positive skin lesions (i.e. fibropapillomas) were identified in Cape mountain zebras (Equus zebra zebra), giraffes (Giraffa camelopardalis) and a sable antelope (Hippotragus niger; van Dyk et al., 2011; Williams et al., 2011). It is reasonable to hypothesize that cross-species infections occur due to the fact that these species are often kept together in herds, and this may allow the infection to spread directly from one animal to another or indirectly via infected flies (Silvestre et al., 2009). It is also reasonable to expect more and more BPV infections in different animal species in the near future in different parts of the world as global warming changes parasite dynamics too. Finally, these data encourage further investigations aiming at demonstrating possible BPV transmission to humans which, so far, has been reported only anecdotally. BPV Genome Organization Bovine papillomaviruses have a non-enveloped structure of 55–60 nm diameter and consist of 72 capsomers organized in a pentameric structure and which forms paracrystalline © 2014 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.

particles in the nuclei of infected cells. It contains a doublestranded circular DNA of approximately 8000 nucleotides complexed with cellular histones, and the major open reading frames are located on the same DNA strand (Lancaster and Olson, 1982). The viral genome consists of three different regions: the long control region (LCR) containing the elements necessary for replication and transcription of the viral DNA, and two regions containing open reading frames (ORFs) corresponding to early and late genes. The proteins encoded by the early genes are designated from E1 to E8. The transformation process is modulated by the three oncogenes, E5, E6 and E7, while the transcription and regulation process is modulated by two regulatory proteins, E1 and E2 (Munger and Howley, 2002). The Xipapillomaviruses constitute the only major exception to the standard gene layout of PVs by lacking the homologue of an E6 gene. In BPV-4, the E6 is replaced by an open reading frame originally termed E8, which later was renamed E5 because of its structural and functional similarities to BPV-1 E5 (Jackson et al., 1991; Faccini et al., 1996). A new ORF replacing E6 gene was also identified in other BPV putative types and termed E8 again, encoding for 75–77 amino acids. This protein contains the 3

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same functional motifs of E5, suggesting similar functions (Tomita et al., 2007b). The structural proteins L1 and L2 encoded by the late genes are expressed once viral genome amplification has been completed (Ozbun and Meyers, 1998). The most highly conserved ORF among PVs is L1 ORF, with 40% of the amino acids identical in distantly related PVs (Baker et al., 1987). This ORF is used in classification and construction of phylogenetic trees. BPV Cutaneous Papillomas and Fibropapillomas To date, at least 12 different BPV types are associated with cutaneous papillomas and fibropapillomas. These lesions can be spread all over the body in cattle (Fig. 1b and c; Corteggio et al., 2013) and are characterized histologically by benign epithelial or epithelial and dermal proliferation. In buffaloes, papillomatosis is associated with either BPV-1 or -2 or both, whose similarity of the BPVs infecting the cattle has been revealed by molecular analysis (Silvestre et al., 2009; Pangty et al., 2010). These benign tumours regress or may undergo neoplastic transformation, as observed for penile carcinoma as well as for periocular carcinoma (Jarrett, 1985a; M.S. Campo, personal communication; IARC Monographs, 2007). In recent years, the pathology of naturally occurring bovine cutaneous papillomatosis has been investigated by many scientists, gaining new important insights into pathogenetic mechanisms (Jarrett, 1985b; Campo, 2006; Bocaneti et al., 2013; Silva et al., 2013a). Studies of the molecular epidemiology of BPVs correlated the identification of the virus with particular tissue

tropism and specific lesions. As a result, BPV-1 has been related to teat, penile and cutaneous fibropapillomas, BPV2 to skin warts and gastrointestinal (GI) fibropapillomas, BPV-3 to skin papillomas, BPV-4 to epithelial papillomas of GI tract and skin, BPV-5 to udder fibropapillomas, BPV6 to teat papillomas, BPV-7 and BPV-8 to cutaneous warts, BPV-9 and BPV-10 to epithelial squamous papilloma lesions on cattle teats, BPV-11 to teat fibropapillomas and the last identified, BPV-13, has been associated with cutaneous papilloma of the ear (Ogawa et al., 2007; Borzacchiello and Roperto, 2008; Hatama et al., 2011; Lunardi et al., 2012; Zhu et al., 2012; Batista et al., 2013). Moreover, the presence of co-infection with various types of BPV is often reported in cattle, and various combinations of multiple BPV infections or simultaneous presence of BPVs in the same lesion has been described (Table 1; Claus et al., 2008; Yaguiu et al., 2008; Schmitt et al., 2010; Carvalho et al., 2012; Batista et al., 2013). Notably, co-infections are also reported in buffaloes (Pangty et al., 2010; Table 1). The importance of BPV infection lies in the fact that papillomas and fibropapillomas on the genital area, teats, prepuce and penis result in difficulties in milking and suckling, ulceration and bleeding in addition to secondary bacterial infection bringing about financial losses (Jarrett, 1985b). The major BPV oncoprotein E5 plays a pivotal role during papilloma formation. The continuous expression of the E5 protein within the basal layer may be responsible for the maintenance of a transformed state and for an active status during the early stage of infection. The presence of the E5 in the granular cell layer where viral capsid proteins are

(a)

(d)

(c)

(b)

Fig. 1. Different localization of bovine papillomaviruses-induced tumours in cattle. (a) oesophageal papilloma (white arrow); (b) cutaneous fibropapillomas (black arrow); (c) multiple rice grain papilloma (black arrow); and (d) urinary bladder cancer (black arrow).

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synthesized and virions are assembled suggests a contribution on the part of E5 in the late stage of the BPV life cycle (Burnett et al., 1992; Bohl et al., 2001). For a large and comprehensive review of the role of BPV E5, refer to Venuti et al., (2011) and Corteggio et al., (2013). Mucosal Papillomas and Cancer Bovine bladder tumours are rare in cattle outside areas where enzootic haematuria occurs and are relatively infrequent in the absence of bracken fern (Pamukcu et al., 1976), despite presumably these cattle being frequently infected with BPV-2. Chronic enzootic haematuria is a syndrome which has been reported both in buffaloes and in cattle and is caused by the interplay between long-term ingestion of bracken fern, immunosuppression and BPV infection. Urinary bladder tumours of both epithelial and mesenchymal origin associated with this syndrome have been described in various parts of the world where both cattle and buffaloes graze on pastures rich in bracken fern (Pteridium aquilinum; Fig. 1d; Jarrett et al., 1978; Borzacchiello and Roperto, 2008; Roperto et al., 2010; Somvanshi et al., 2012). The implication of BPV-1 and BPV-2 in bladder carcinogenesis has been recognized for many years, and the interaction between the carcinogenic principles of fern and BPV has been experimentally reproduced (Table 1; Campo et al., 1992). It has been demonstrated unequivocally that in samples collected from cattle from different countries where CEH was reported, such as Portugal, Turkey, Italy, India, Romania and Brazil, E5 protein was present in the transformed cells (Borzacchiello et al., 2003a; Balcos et al., 2008; Resendes et al., 2011; Roperto et al., 2013b), thus supporting the causative role of this oncoprotein. The presence of BPV-2 E5 oncoprotein in bubaline urothelial neoplastic cells has been established by various groups, and a recent study clearly indicates that a complete life cycle of BPV-2 also occurs in bubaline urinary bladder cancer given that the expression of BPV-2 L1 protein was detected (Maiolino et al., 2013). It is believed that urinary bladder tumours do not lead to productive infection by BPV-2; therefore, it has been suggested that the permanent episomal condition of viral DNA could be responsible for the determination of an abortive infection (Campo et al., 1992; Campo, 2002). Very recently, Roperto et al. (2013a) have demonstrated, for the first time, in both cattle and buffaloes, that the urothelial cells of urinary bladder cancer are permissive for a productive infection. It has been hypothesized that the overexpression of BPV-2 E2 in buffalo urinary bladder neoplastic cells may be responsible for a high expression of BPV oncogenes © 2014 Blackwell Verlag GmbH • Transboundary and Emerging Diseases.

Bovine Papillomavirus

exposing the urothelial cells to a considerable amount of oncoproteins; a similar action was recently observed also in human counterpart (Alvarez et al., 2010; Roperto et al., 2013a,b). Interestingly, specific viral E5 oncoprotein was detected in lymphocytes of cattle suffering from urinary bladder tumours, suggesting that bloodstream represents a reservoir of viral infection (Roperto et al., 2008, 2012). The classification and the characterization of the urothelium lesions associated with CEH have been extensively studied. Roperto et al. (2010) established a classification system for bovine bladder tumours based on the World Health Organization (WHO) scheme, describing four distinct growth patterns of bovine urothelial tumours and tumour-like lesions: flat, exophytic or papillary, endophytic and invasive. The most common urothelial tumour seen is the low-grade carcinoma, followed by carcinoma in situ, papillomas, papillary urothelial neoplasms of low malignant potential, while the high-grade carcinomas and the low- and high-grade invasive tumours are less commonly diagnosed; BPV has been detected in all the aforementioned lesions, thus suggesting that it is associated with bladder cancer independently of the histotypes (Roperto et al., 2010). Similar lesions were described also in buffaloes, demonstrating that BPV-2 is involved in urothelial bladder carcinogenesis regardless of bovid species (Maiolino et al., 2013). Another mucosal site of BPV infection in large ruminants is the upper and lower GI tract, in which papillomas can extend from the mouth and tongue to the oesophagus, rumen and reticulum. This can subsequently induce difficulty in feeding and breathing that may be fatal (Fig. 1a; Campo, 1997; Tsirimonaki et al., 2003; Dong et al., 2013). Normally, in immunocompetent animals, the cell-mediated immune response is able to reject the papillomas (Knowles et al., 1996), but in cattle grazing bracken fern (due to immunosuppressants present in the plant), the papillomas persist and may be transformed into malignant carcinomas, including squamous cell carcinomas (Hamada et al., 1989; Campo et al., 1994; Borzacchiello et al., 2003b; Masuda et al., 2011). In cattle grazing pastures where bracken fern is absent, the occurrence of the GI malignancies is rarely reported (Plummer, 1956; Bastianello, 1982). Campo (1997) demonstrated the association of BPV-4 with GI papillomas and squamous cell carcinoma, and this association has been reported in various countries (Campo et al., 1980; Borzacchiello et al., 2003b). In a comprehensive study of bovine neoplasia in Brazil, the alimentary tract was reported as the most commonly affected site in cattle grazing in areas rich in bracken fern and the majority of tumours were malignant (Lucena et al., 2011). As GI papillomas are rarely reported in areas lacking in bracken fern and usually regress due to a competent 5

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immune response, BPV infection is likely to be considered necessary for the development of these hyperproliferative lesions, but not sufficient to induce cancer, where the chronic exposure to immunosuppressants of bracken fern is essential for viral persistence and malignant progression.

and similar suggestions come from BPV-4 L2 multimeric vaccines in bovines (Shafti-Keramat et al., 2009; Jagu et al., 2011; Hainisch et al., 2012). The development of a prophylactic and/or therapeutic vaccine remains a challenge for scientists.

Vaccines

Conclusions

Proliferative epithelial lesions induced by PVs generally regress spontaneously due to cell-mediated immune responses. However, the viruses have evolved mechanisms to avoid immune attack directly (O’Brien and Campo, 2003). Surprisingly, the immune response of cattle and buffaloes to BPV infection is poor. A plausible hypothesis might be that the virus life cycle is restricted to the epithelium and therefore fails to have contact with the immune system (Campo, 2006). In BPV E5-expressing papilloma cells, the major histocompatibility complex (MHC) expression is inhibited. This is one of the mechanisms by which the BPV avoids the immune system response (Araibi et al., 2004). As the preparation of traditional killed or attenuated live vaccines from cultured BPVs is not possible, different systems have been challenged, such as yeast, insect cell and plants, to produce L1- and L2-based vaccines (Kirnbauer et al., 1992; Campo, 2003). The L1 and L2 proteins of BPV-2 produced in Escherichia coli as beta-galactosidase fusion proteins and used to vaccinate calves both prophylactically and therapeutically showed that, while the L2 fusion protein was very effective in promoting tumour rejection, the animals vaccinated with L1 responded rapidly with production of serumneutralizing antibodies. Therefore, in calves, L1 vaccine prevented BPV-2-induced tumour formation only if it was given before the challenge, whereas L2 promoted tumour rejection irrespective of whether it was administered before or after the challenge (Jarrett et al., 1991). Recently, BPV-1 L1 protein was transiently expressed in Nicotiana benthamiana, and it was proven that, in plant, the L1 codon optimization had higher level of expression when compared to its non-optimized counterpart and showed that the pure L1 extracted from the leaf had selfassembled into virus-like particles (VLPs). Subsequently, these VLPs gave a highly specific and strong immune response when administered to rabbits, and they might thus be considered a possible vaccine candidate against BPV-1 L1 produced in plant (Love et al., 2012). In humans and several animal species, immunization with VLPs of papillomaviruses has been shown to provide efficient protection from PV infection (Zinkernagel, 2003; Villa et al., 2005; Schiller, 2007). Recent studies conducted on horses demonstrated that BPV-1 L1 protein VLPs constitute a safe and highly immunogenic vaccine candidate,

Bovine papillomaviruses are oncogenic viruses affecting both epithelial and mucosal tissues of bovines. The host spectrum and the specific tropism of each BPV type are well established; however, in the recent years, this virus broke this ‘paradigm’, as unusual different types have been detected in unusual sites and different species. Thus, the epidemiology and the species specificity of BPV are changing quickly, and many new aspects are emerging. It is expected that, in a few years time, more and more BPV genotypes will be discovered and the relationship between new and ‘old’ genotypes and phenotypes will appear less nebulous. New insights with respect to viral transmission are also remarkable, with some evidences of a possible vertical transmission through blood, reproductive tract and milk. Finally, many new facets of transforming viral activity and host response to viral threat are being studied, so that the molecular scenario behind BPV oncogenic potential in bovine tumours will be better clarified.

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Bam, J., P. Kumar, G. D. Leishangthem, A. Saikia, and R. Somvanshi, 2012: Spontaneous cutaneous papillomatosis in yaks and detection and quantification of bovine papillomavirus -1 and -2. Transbound. Emerg. Dis. 60, 475–480. Bastianello, S. S., 1982: A survey on neoplasia in domestic species over a 40-year period from 1935 to 1974 in the Republic of South Africa. I. Tumours occurring in cattle. Onderstepoort J. Vet. Res. 49, 195–204. Batista, M. V., M. A. Silva, N. E. Pontes, M. C. Reis, A. Corteggio, R. S. Castro, G. Borzacchiello, V. Q. Balbino, and A. C. Freitas, 2013: Molecular epidemiology of bovine papillomatosis and the identification of a putative new virus type in Brazilian cattle. Vet. J. 197, 368–373. Bernard, H. U., R. D. Burk, Z. Chen, K. van Doorslaer, H. Hausen, and E. M. de Villiers, 2010: Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 401, 70–79. Bocaneti, F., G. Altamura, A. Corteggio, M. Martano, F. Roperto, E. Velescu, and G. Borzacchiello, 2013: Expression of platelet derived growth factor beta receptor, its activation and downstream signals in bovine cutaneous fibropapillomas. Res. Vet. Sci. 94, 596–601. Bohl, J., B. Hull, and S. B. Vande Pol, 2001: Cooperative transformation and coexpression of bovine papillomavirus type 1 E5 and E7 proteins. J. Virol. 75, 513–521. Borzacchiello, G., and A. Corteggio, 2009: Equine sarcoid: state of the art. Ippologia 20, 7–14. Borzacchiello, G., and F. Roperto, 2008: Bovine papillomaviruses, papillomas and cancer in cattle. Vet. Res. 39, 45. Borzacchiello, G., G. Iovane, M. L. Marcante, F. Poggiali, F. Roperto, S. Roperto, and A. Venuti, 2003a: Presence of bovine papillomavirus type 2 DNA and expression of the viral oncoprotein E5 in naturally occurring urinary bladder tumours in cows. J. Gen. Virol. 84, 2921–2926. Borzacchiello, G., V. Ambrosio, S. Roperto, F. Poggiali, E. Tsirimonakis, A. Venuti, M. S. Campo, and F. Roperto, 2003b: Bovine papillomavirus type 4 in oesophageal papillomas of cattle from the south of Italy. J. Comp. Path. 128, 203–206. Burnett, S., N. Jareborg, and D. DiMaio, 1992: Localization of bovine papillomavirus type 1 E5 protein to transformed basal keratinocytes and permissive differentiated cells in fibropapilloma tissue. Proc. Natl. Acad. Sci. U. S. A. 89, 5665–5669. Campo, M. S., 1992: Cell transformation by animal papillomaviruses. J. Gen. Virol. 73(Pt 2), 217–222. Campo, M. S., 1995: Infection by bovine papillomavirus and prospects for vaccination. Trends Microbiol. 3, 92–97. Campo, M. S., 1997: Bovine papillomavirus and cancer. Vet. J. 154, 175–188. Campo, M. S., 2002: Animal models of papillomavirus pathogenesis. Virus Res. 89, 249–261. Campo, M. S., 2003: Papillomavirus and disease in humans and animals. Vet. Comp. Oncol. 1, 3–14. Campo, M. S., 2006: Papillomavirus Research: From Natural History to Vaccines and Beyond. Caister Academic, Wymondham.

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