PAPILLOMAVIRIDAE

Current author:
J S MUNDAY - Professor of Veterinary Pathology, BVSc, PhD, Dipl ACVP, School of Veterinary Science, Massey University, Tennent Drive, Palmerston North, Manawatu, 4410, New Zealand

Introduction

Papillomaviruses were previously classified along with Polyomaviruses within the Papovaviridae family. However, these viruses are now classified into the two separate families of Papillomaviridae and Polyomaviridae. As polyomaviruses are not considered pathogenic in livestock, these are not discussed further.

Papillomaviruses are associated with important diseases in bovine, ovine and equine species These viruses are considered a rare cause of disease in goats and, although pigs are infected by papillomaviruses, they have not been associated with disease in this species. In other domestic species, papillomaviruses are also associated with oral papillomas, cutaneous papillomas, cutaneous pigmented plaques, and squamous cell carcinomas (SCCs) in dogs and oral papillomas, cutaneous viral plaques/Bowenoid in situ carcinomas, SCCs, and sarcoids in cats (Table 1).^{22, 25}

Biology of papillomaviruses

Papillomaviruses are small, non-enveloped, icosahedral viruses. Their circular double-stranded DNA genome is around 8000 base pairs long and includes five or six early (E) and two late (L) open reading frames (ORF) (Figure 1). Papillomaviruses are classified using the L1 ORF sequence. Papillomaviruses within the same genus have greater than 60 per cent L1 ORF similarity and typically demonstrate similar host, location, and behavioral characteristics. Different papillomavirus types have less than 90 per cent similarity in their L1 ORF.⁴ The Papillomaviridae family currently includes 49 genera¹⁶ that contain numerous different papillomavirus types that infect a wide variety of animals including mammals, reptiles, and birds (Figure 2).²³ However, short sequences of additional papillomavirus types have been amplified from many domestic species suggesting that new papillomavirus types are likely to be recognized in the future. Papillomaviruses have co-evolved with their hosts over a long time and the vast majority of papillomaviruses are strictly species specific. Currently, the bovine Deltapapillomaviruses are the only papillomaviruses known to be able to infect more than one species.^{24, 26}

Infections by papillomaviruses are generally limited to stratified epithelium. The Deltapapillomaviruses are unique because they can also infect mesenchymal cells, although these cells probably do not permit virus replication.¹⁸ Papillomaviruses can be spread by direct contact. Additionally, as these viruses are able to survive for an extended time in the environment, they can also be spread indirectly. There is some evidence that papillomaviruses may also be able to be spread via biting flies or other insect vectors.¹³ Once the papillomavirus comes into contact with a mucocutaneous epithelium, the presence of microabrasions allows infection of basal cells resulting in the production of small numbers (10-200) of circular papillomavirus DNA copies (episomes) which are maintained in the basal cells as they replicate.³⁰ While basal cell replication maintains the infection, the viral life-cycle is only completed when an infected cell undergoes terminal differentiation.⁹ This differentiation of a basal cell normally results in the cell becoming post-mitotic with subsequent loss of the nuclear machinery. To prevent the suprabasilar cell from leaving the cell cycle, the papillomavirus produces the E6 and E7 proteins that induce cell replication. Cell replication maintains the cell nuclear machinery that is required for papillomavirus replication as well as expanding the pool of infected cells within the epithelium, greatly increasing viral replication.¹¹ The papillomavirus capsid proteins (L1 and L2) are expressed and viral assembly occurs as the infected cell reaches the upper epithelium. Papillomavirus-laden mature keratinocytes are sloughed from the epithelial surface. Papillomaviruses do not cause cell lysis, but the normal degradation of these sloughed cells releases infectious virions.¹¹

Pathogenesis of papillomavirus disease

The clinical presentation of a papillomavirus infection is largely determined by the degree of cell proliferation induced by the individual papillomavirus. Most papillomavirus types only mildly increase cell proliferation and papillomavirus replication occurs slowly in the absence of any visible lesions.¹¹ Alternatively, a minority of papillomavirus types markedly increase cell replication resulting in rapid production of large numbers of viral particles. Such infections cause marked epithelial hyperplasia that is visible clinically as a papilloma (wart).²¹

As papillomaviruses do not cause cell lysis they are generally of minimal adverse impact to the host and papillomavirus infections often illicit only a weak immune response.¹⁰ The immune reaction is further reduced because the majority of papillomavirus proteins are only expressed within the external epithelial layers. Furthermore, some papillomavirus proteins have been found to potentially interfere with an immune response.⁸ When an immune reaction occurs, the response can be subdivided into humoral and cell-mediated components. The production of circulating IgG antibodies blocks entry of the papillomavirus into the basal cells preventing further infections by this papillomavirus type, although...