Papillomaviruses (PVs) are established agents of human and animal cancers. They infect cutaneous and mucous epithelia. High Risk (HR) Human PVs (HPVs) are consistently associated with cancer of the uterine cervix, but are also involved in the etiopathogenesis of other cancer types. The early oncoproteins of PVs: E5, E6 and E7 are known to contribute to tumour progression. While the oncogenic activities of E6 and E7 are well characterised, the role of E5 is still rather nebulous. The widespread causal association of PVs with cancer makes their study worthwhile not only in humans but also in animal model systems. The Bovine PV (BPV) system has been the most useful animal model in understanding the oncogenic potential of PVs due to the pivotal role of its E5 oncoprotein in cell transformation. This review will highlight the differences between HPV-16 E5 (16E5) and E5 from other PVs, primarily from BPV. It will discuss the targeting of E5 as a possible therapeutic agent.
Bovine papillomavirus (BPV) is perhaps the most extensively studied animal papillomavirus. In cattle BPVs induce benign tumours of cutaneous or mucosal epithelia, called papillomas or warts. Cattle papillomas are benign tumours and generally regress without eliciting any serious clinical problems in the host, but occasionally persist and provide the focus for malignant transformation to squamous cell carcinoma, as in the case of cancer of the urinary bladder and cancer of the upper alimentary canal. BPV is the only papillomavirus that jumps species: the virus also infects equids, and gives rise to fibroblastic tumours called sarcoids. Sarcoids very rarely regress, more often they persist and can be locally aggressive. These tumours are the most common dermatological tumour of equids worldwide. The purpose of this review is to discuss the biology of BPV, the biology of bovine tumours and equine sarcoids, and present the current understanding of BPV in tumour pathogenesis in its natural host, cattle, and in its heterologous host, equids. Finally, the use of anti-BPV vaccines as a therapy for equine sarcoids will be discussed. Only limited information on the clinical or pathological aspects of either bovine or equine tumours will be provided as this subject has been extensively addressed previously.
The equine sarcoid, a locally aggressive, fibroblastic skin tumour, is the most common dermatological neoplasm reported in horses; there is no consistently effective therapy. It is widely accepted that bovine papillomavirus (BPV) types 1 and 2 are associated with the pathogenesis of sarcoid disease. Most sarcoids appear to contain detectable viral DNA and RNA and are also known to express the BPV types 1 and 2 major transforming protein, E5, but appear not to produce infectious virions. While the mode of transmission of infection has not been elucidated, viral gene expression, in particular of E5, may contribute to virus persistence and disease pathogenesis by downregulating MHC class I expression. Here, the pathology and epidemiology of the sarcoid and its association with BPV is reviewed; the transforming functions of the BPV oncoproteins and their possible role in sarcoid pathogenesis are discussed; and the practical implications of BPV infection for diagnostic and therapeutic purposes are considered.
Papillomaviruses (PVs) are small DNA tumor viruses that infect the epithelia of humans and animals, causing benign hyperproliferative lesions. In most cases, PV infections are cleared after several months following activation of the host immune system against viral antigen. 1 However, occasionally the lesions do not regress and can progress to cancer. Certain PVs are more commonly associated with malignancy, including the human PV (HPV) types 16 and 18, high-risk viruses for the development of cervical cancer in women, 2 and bovine PV (BPV) type 4, associated with carcinomas of the alimentary canal in cattle. 3 Persistent viral infection is required for neoplastic progression and failure of virus clearance is attributed to a poor immunologic response.The PV genome encodes 3 transforming proteins, E5, E6 and E7. E5 is a small hydrophobic protein ranging in size from 42 amino acid residues in BPV-4 to 83 amino acid residues in HPV-16. E6 and E7 are the main transforming proteins of HPV. 4,5 E5 is the major transforming protein of BPV and plays a lesser role in transformation by HPV. 6 While E6 and E7 are expressed throughout the course of the disease and are necessary for the maintenance of a transformed phenotype, E5 is expressed during the early stages of infection and its expression is often, but not always, extinguished as the lesion progresses toward malignancy. 6 These characteristics point to a role of E5 in establishment of PV infection and the initiation of cell transformation.The E5 protein is localized in the Golgi apparatus (GA), endoplasmic reticulum and occasionally the plasma membrane of the host cell. Its localization in the endomembrane compartments, where it interacts with the vacuolar ATPase 16k ductin/ subunit c, 7-9 is deemed responsible for the lack of acidification of the GA and endolysosomes and the consequent impaired functions of these organelles. 10,11 We have shown that one of the outcomes of BPV E5 expression in primary cells is the retention of major histocompatibility (MHC) class I complexes in the GA and the inhibition of their transport to the cell surface. 12,13 Furthermore, BPV E5 inhibits both transcription of the MHC class I heavy chain gene and affects the stability of the heavy chain protein. 12 In this study, we show that HPV-16 E5 also prevents the transport of MHC (HLA) class I complexes to the cell surface due to retention in the GA. Moreover, we show that HPV-16 E5 selectively downregulates HLA-A and HLA-B molecules on the cell surface but does not affect the transport of HLA-C and HLA-E. These studies identify a potential novel mechanism by which PV-infected cells may avoid clearance by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, aiding in the establishment and persistence of PV infection. Material and methods HPV-16 E5 expression constructsThe E5 ORF was cloned into 3 expression plasmids: pcDNA3 (Invitrogen, Glasgow, U.K.), under the transcriptional control of the universal cytomegalovirus (CMV) immediate early promoter (pc-16E5); pL2, under control o...
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