Introduction

Classification

Taxonomy

• Papovaviridae family to include papillomas, polyomaviruses and vacuolating agents.

Etymology

• L: papilla - nipple.
• Gk: oma - tumor, abnormal growth.

Active Forms

Clinical Effects

Epidemiology

Lifecycle

• Little is definitively known.
• In general, replication is dependent on terminal differentiation of the epithelial cell due to interaction with specific cell factors expressed on differentiation of the cell:
  • The virus infects basal cell of epithelium often through minor trauma to the epithelium.
  • The viruses attach to the cell (assumed through L1) and is taken up by endocytosis, then transported to the nucleus where plasmid replication takes place.
  • Papillomaviruses will undergo DNA replication in the basal cell. DNA is maintained as a stable multicopy plasmid which replicates during the S phase of the cell cycle.
  • Virus infection induces cellular proliferation, hence formation of the wart. As the epithelial cell differentiates to a keratinocyte and moves to the epidermal surface, virus replication switches to vegetative DNA replication and virion formation in the nucleus.
  • Nuclear breakdown occurs and the virus is released.
• Entrance into keratinocytes through traumatic lesions allows viral replication.
• For CRPV different mRNA transcripts are present (E1 protein, E2 protein, E6 protein, E7 protein, L1 protein and L2 protein transcripts) in latent viruses. Only E6 and E7 oncoprotein transcripts can be induced to form papillomas.

Transmission

• Experimental infection by scarification of the skin.
• Natural transmission is by direct contact: infective particles shed from oral lesions contact the oral mucosa of the naive animal for ROPV. The mucosal integrity must be compromised in order for the virus to enter.
• For CRPV, transmission is principally via viral inoculation by biting arthropod vectors, including ticks.

Pathological effects

• Age-resistance in most animals; lesions spontaneously regress in rabbit oral papillomatosis.
• Benign warts in rabbit oral papillomatosis; show no tendency to malignancy.
• In CRPV, papillomas often spontaneously regress after several months, however, in approximately 25% of naturally infected Cottontails the lesions undergo malignant transformation into squamous cell carcinomas Cutaneous neoplasia. In approximately 75% of experimentally infected domestic rabbits, lesions undergo malignant transformation.

Other Host Effects

• Species specific.
• Possible progression to malignancy in CRPV:
  • In general, transformation properties of the viral proteins themselves do not cause malignant transformation but allows cells to proliferate more.
  • Other cofactors can induce cellular genomic mutations, eg in CRPV, it was shown experimentally that malignant progression was more frequent and more rapid in lesions painted with a co-carcinogen such as methylcholanthrene or coal-tar.

Control

Control via animal

• Isolation of infected animals would prevent spread; however, this is not generally necessary.

Control via chemotherapies

• For CRPV, topical cidofovir has also been used to treat CPRV in the laboratory setting. It led to elimination of large papillomas over the 6–8-week treatment period, however, recurrences occurred within 1-8 weeks after stopping the treatment in approximately 50% of the cases.

Vaccination

• Autogenous vaccines available for some papillomaviruses, but of dubious efficacy.

Other countermeasures

• For CRPV other countermeasures include:
  • Arthropod vector control.
  • Screens to keep out insects
  • Flea control.
  • Keeping rabbits indoors.

Diagnosis

Further Reading

Publications

Refereed papers

• Recent references from PubMed and VetMedResource.
• Kerr P J & Donnelly T M (2013) Viral infections of rabbits. Vet Clin Exot Anim 16 (2), 437-468 PubMed.
• Howley P M (2006) Warts, cancer and ubiquitylation: lessons from the papillomaviruses. Trans Am Clin Climatol Assoc 117, 113-127 PubMed.
• Rous P & Beard J W (1936) The carcinogenic effect of a virus upon tarred skin. Sci 83 (2159), 468-469 PubMed.
• Rous P & Beard J W (1935) The progression to carcinoma of virus-induced rabbit papillomas (Shope). J Exp Med 62 (4), 523-548 PubMed.

Other sources of information

• DiGiacomo R F & Mare C J (1994) Viral Diseases. In: The Biology of the Laboratory Rabbit. Eds: Manning P J, Ringler D H & Newcomer C E. 2nd edn. Academic Press, USA. pp 171-204.