Bovine papillomaviruses, papillomas and cancer in cattle Giuseppe Borzacchiello, Franco Roperto To cite this version: Giuseppe Borzacchiello, Franco Roperto. Bovine papillomaviruses, papillomas and cancer in cattle. Veterinary Research, BioMed Central, 2008, 39 (5), pp.1. 10.1051/vetres:2008022. hal-00902936 HAL Id: hal-00902936 https://hal.archives-ouvertes.fr/hal-00902936 Submitted on 1 Jan 2008 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Vet. Res. (2008) 39:45 www.vetres.org DOI: 10.1051/vetres:2008022 C INRA, EDP Sciences, 2008 Review article Bovine papillomaviruses, papillomas and cancer in cattle Giuseppe Borzacchiello*,FrancoRoperto Department of Pathology and Animal health, Faculty of Veterinary Medicine, Naples University “Federico II”, Via F. Delpino, 1 – 80137, Naples, Italy (Received 27 November 2007; accepted 7 May 2008) Abstract – Bovine papillomaviruses (BPV) are DNA oncogenic viruses inducing hyperplastic benign lesions of both cutaneous and mucosal epithelia in cattle. Ten (BPV 1-10) different viral genotypes have been characterised so far. BPV 1-10 are all strictly species-specific but BPV 1/2 may also infect equids inducing fibroblastic tumours. These benign lesions generally regress but may also occasionally persist, leading to a high risk of evolving into cancer, particularly in the presence of environmental carcinogenic co-factors. Among these, bracken fern is the most extensively studied. The synergism between immunosuppressants and carcinogenic principles from bracken fern and the virus has been experimentally demonstrated for both urinary bladder and alimentary canal cancer in cows whose diets were based on this plant. BPV associated tumours have veterinary and agricultural relevance in their own right, although they have also been studied as a relevant model of Human papillomavirus (HPV). Recent insights into BPV biology have paved the way to new fields of speculation on the role of these viruses in neoplastic transformation of cells other than epithelial ones. This review will briefly summarise BPV genome organization, will describe in greater detail the functions of viral oncoproteins, the interaction between the virus and co-carcinogens in tumour development; relevant aspects of immunity and vaccines will also be discussed. cancer / cattle / co-factor / Papillomavirus /viruses Table of contents 1. Introduction................................................................................................ 1 2. The virus: structure, genome and control of transcription............................................... 2 3. Viraloncoproteins......................................................................................... 3 4. Lateproteins............................................................................................... 5 5. NaturalhistoryofBPVinfection:papillomasandfibropapillomas..................................... 5 6. Bracken fern as a cofactor for carcinogenesis ........................................................... 7 7. BPV-4 and gastrointestinal tumours ...................................................................... 8 8. BPV-1/2 and urinary bladder tumours.................................................................... 9 9. Immunity and vaccines.................................................................................... 11 10.Conclusions................................................................................................ 13 1. INTRODUCTION hyperproliferative lesions of both mucosal and cutaneous epithelia [62, 130, 131]. Bovine papillomaviruses (BPV) belong to BPV are strictly species-specific, and, the Papillomavirus (PV) genus. These are even in experimental conditions, do not infect small DNA viruses infecting humans as any host other than the natural one. The well as many domestic and wild animal only known case of cross-species infection species, including birds, causing benign is for horses and other equids by BPV type * Corresponding author: [email protected] 1 (BPV-1) or BPV type 2 (BPV-2) [36]. Article available at http://www.vetres.org or http://dx.doi.org/10.1051/vetres:2008022 Vet. Res. (2008) 39:45 G. Borzacchiello and F. Roperto BPV infections usually regress, but may occa- The BPV virion is a non-enveloped icosa- sionally evolve into cancer of both epithelial hedral structure of 55–60 nm diameter which and mesenchymal origin. Healthy cattle nor- forms paracrystalline particles in the nuclei of mally recover from papillomas, but in animals infected cells; it contains a double-stranded grazing on bracken fern (Pteridium aquil- covalentely closed circular DNA of approx- inum), there is a good correlation between imately 8000 nucleotides complexed with persistent papillomatosis and cancer [23, 66]. cellular histones. Cattle feeding on bracken fern develop upper The structure of the virion has been recently alimentary canal and urinary bladder cancers, described with an atomic model showing the the former being associated with the presence L1 protein to be exposed on the viral surface, of the BPV-4 and the latter with BPV-2. thus suggesting to have a role in infection BPV induces diseases of considerable and in immunogenicity [87]. Three different veterinary importance in farm animals, but has regions compose the genome: the long control also an enormous value as an in vivo model region (LCR) containing the elements neces- for HPV. In fact, due to the high species- sary for replication and transcription of the specificity of Papillomaviruses, virologists viral DNA, and two regions containing open have used BPV as a model for the study of reading frames (ORF) corresponding to early HPV infection, its interaction with the host and and late genes. The early genes encode for with environmental co-factors. proteins involved in both viral DNA replica- tion and transcription and cell transformation; the late genes encode for capsid proteins. The 2. THE VIRUS: STRUCTURE, GENOME genomes of BPV-3, BPV-4 and BPV-6 lack the AND CONTROL OF TRANSCRIPTION E6 ORF–which has been replaced by the E5 Ten BPV types (BPV 1-10) have been (originally defined as E8), whereas, similarly characterised and associated with differ- to most PV types, BPV-1, BPV-2 and BPV-5 ent histopathological lesions. The different still retain this gene. LCR is a non-coding genotypes have been classified into three genome region of approximatively 500–1000 genera [47]: nucleotides (nt) between the 3’-end of the late Xipapillomaviruses encompassing the pure ORF and the 5’-end of the early ORF. LCR epitheliotropic BPV-3; BPV-4 and BPV-6; contains all the regulatory signals for both Deltapapillomaviruses encompassing BPV-1 viral DNA replication and transcription. The and BPV-2, associated with fibropapillomas LCR of BPV-1, BPV-2 and BPV-5 has twelve (i.e. benign tumours of both the epithelium and E2 binding sites, whereas four E2 binding underlying derma) and Epsilonpapillomavirus sites are recognised in BPV-3, BPV-4 and comprising BPV-5 whose genome seems to BPV-6 LCR. The binding of the E2(2) and share similarities with the former two BPV E2(3) sites with E2 proteins induces transcrip- groups. In addition, sixteen novel putative tional repression, whereas the binding of the BPV have been characterised by sequence E2(1) and dE2 sites results in transcriptional determination of the highly conserved L1 activation. In addition, the binding of E2(1) region and by phylogenetic analysis [6]. Two with E2(2) is more stable than complexes novel BPV were characterised further and the formed by the E2(3) and E2(4) sites [64]. phylogenetic analysis showed that both viruses However, the BPV-4 LCR has multiple pos- were new BPV types: one was designated itive and negative regulatory elements able as BPV-7 and classified as a member of a to act independently of E2. Among these, the new PV genus, and the other was designated best characterised cellular transcription factor as BPV-8 and classified as a member of the is PEBP2, which binds to the E2(2) site [64]. Epsilonpapillomavirus genus [95, 134]. While the E1 protein functions in viral Recently, Hamata et al. [59] identified two DNA replication [76], E2 binding to LCR new BPV types belonging to the genus Xipa- activates or represses transcription of the pillomavirus designed as BPV-9 and BPV-10. viral genes. Another relevant function of Page2of19(page number not for citation purpose) Viral tumour Vet. Res. (2008) 39:45 E2 is its ability to segregate episomal BPV genomes to daughter cells, following cell divi- sion, by tethering them to mitotic chromo- somes, thus ensuring equal distribution and retention of viral DNA [12]. The BPV-1 E2 protein associates with mitotic chromatin via the aminoterminal domain of the pro- tein and once bound is able to interact with the viral genomes via the carboxyl termi- nus dimerisation and DNA binding domain [1, 63, 78, 125]. For the association of the E2 with mitotic chromatin, the phosphorylation status of the E2 protein is not required [11], and it is likely that the cellular protein Brd4, is responsible for the interaction