Animal models of papillomavirus pathogenesis.

Abstract: Tumorigenesis due to papillomavirus (PV) infection was first demonstrated in rabbits and cattle early last century. Despite the evidence obtained in animals, the role of viruses in human cancer was dismissed as irrelevant. It took a paradigm shift in the late 1970s for some viruses to be recognised as 'tumour viruses' in humans, and in 1995, more than 60 years after Rous's first demonstration of CRPV oncogenicity, WHO officially declared that 'HPV-16 and HPV-18 are carcinogenic to humans'. Experimental studies with animal PVs have been a determining factor in this decision. Animal PVs have been studied both as agents of disease in animals and as models of human PV infection. In addition to the study of PV infection in whole animals, in vitro studies with animal PV proteins have contributed greatly to the understanding of the mechanisms of cell transformation. Animal PVs cause distressing diseases in both farm and companion animals, such as teat papillomatosis in cattle, equine sarcoids and canine oral papillomatosis and there is an urgent need to understand the pathogenesis of these problematic infections. Persistent and florid teat papillomatosis in cows can lead to mastitis, prevent the suckling of calves and make milking impossible; heavily affected animals are culled and so occasionally are whole herds. Equine sarcoids are often recurrent and untreatable and lead to loss of valuable animals. Canine oral papillomatosis can be very extensive and persistent and lead to great distress. Thus the continuing research in the biology of animal PVs is amply justified. BPVs and CRPV have been for many years the model systems with which to study the biology of HPV. Induction of papillomas and their neoplastic progression has been experimentally demonstrated and reproduced in cattle and rabbits, and virus-cofactor interactions have been elucidated in these systems. With the advancements in molecular and cell culture techniques, the direct study of HPV has become less problematic and understandably research efforts have shifted in focus from animal to human PVs. However, there are still areas in which studies on animal PVs will continue to provide answers to questions pertaining to virus biology. One of these questions is the involvement of HPV in oesophageal and bladder cancer in humans as is the case for BPV in cattle. Another is the site of viral latency. Lymphocytes have been proposed as a site of latency for both BPV and HPV but only experiments performed in animals could clarify this point. Animal PVs have been instrumental in the development of vaccines as cattle, rabbit and more recently dog all provide the opportunity to study vaccination in the natural host. Several anti-HPV vaccines, both prophylactic and therapeutic, based on those developed in animals, are now in clinical trials with encouraging results. In vitro studies with two animal PV early proteins, the transcriptional regulator E2 and the oncoprotein E5, among others, have contributed to the elucidation of viral gene control and cell transformation. BPV E2 was the first viral product to be identified as a transcriptional regulator; more recently, its association with mitotic chromosomes has been suggested as a mechanism for the partition of viral genomes between daughter cells, and its L2-mediated localisation in the sub-nuclear compartments PODs is believed to favour viral DNA encapsidation. E5 is the major transforming protein of several BPVs. Many of the function of E5 proteins have been first established for BPV E5 and later validated for HPV E5. E5 interacts with 16k ductin/subunit c and this interaction is deemed responsible for the down-regulation of gap junction intercellular communication and the inhibition of acidification of endomembranes. E5 activates growth factor receptors and numerous kinases, including cdks, and down-regulates expression of MHC class I. Thus E5 would help the establishment of viral infection by promoting both cell proliferation and immune evasion. Despite the extensive studies on vaccination in animals, E5 has not been tried inE5 has not been tried in animal models as a possible anti-papillomavirus vaccine. A recent study has reported that vaccination of mice with HPV-16 E5 in a recombinant adenovirus reduced the growth of tumours induced by E5-expressing cells. Perhaps this is an instance in which work on animal PVs should follow HPV and the potential for E5 vaccination should be validated in naturally occurring animal models.