The rabbit papillomavirus model: a valuable tool to study viral–host interactions

Abstract

One contribution of 16 to a theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.Cottontail rabbit papillomavirus (CRPV) was the first DNA virus shown to be tumorigenic. The virus has since been renamed and is officially known as Sylvilagus floridanus papillomavirus 1 (SfPV1). Since its inception as a surrogate preclinical model for high-risk human papillomavirus (HPV) infections, the SfPV1/rabbit model has been widely used to study viralhost interactions and has played a pivotal role in the successful development of three prophylactic virus-like particle vaccines. In this review, we will focus on the use of the model to gain a better understanding of viral pathogenesis, gene function and host immune responses to viral infections. We will discuss the application of the model in HPV-associated vaccine testing, in therapeutic vaccine development (using our novel HLA-A2.1 transgenic rabbits) and in the development and validation of novel anti-viral and anti-tumour compounds. Our goal is to demonstrate the role the SfPV1/ rabbit model has played, and continues to play, in helping to unravel the intricacies of papillomavirus infections and to develop tools to thwart the disease.This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.

Papillomavirus can be transmitted through the blood and produce infections in blood recipients: Evidence from two animal models

“…Therefore, a human papillomavirus cannot infect any animal [50]. Our laboratory has expertise in both the CRPV/rabbit and the MmuPV1/mouse models [15,16]. Armed with these preclinical models, we demonstrated that ( 1) Viral sequences could be detected in the blood of infected animals; (2) Virus introduced into the blood yielded tumours at both cutaneous and mucosal sites; (3) CRPV DNA introduced into the blood yielded papillomas at prepared skin sites; (4) Similar mechanisms are used for infections via the blood and by direct application of virus to the skin as determined by RNA-seq analysis; (5) Transfusion of blood from an animal that had received virus via intravenous infection to a naïve sibling resulted in papillomas in the transfusion recipient; (6) Virus introduced via intravenous delivery yielded infections at the stomach as well as the normally permissive sites, and (7) Blood from animals with active infections could induce infections in naïve mice when transfused into these animals.…”

“…For IHC, an in-house anti-MmuPV1 L1 monoclonal antibody (MPV.B9) and a rabbit polyclonal antibody against MmuPV1 E4 protein (a generous gift from Dr John Doorbar) were used on FFPE sections. For ISH, a biotin labelled 2794 bp EcoRV/SacII sub-genome fragment of CRPV and 3913 bp EcoRV/BamHI sub-genomic fragment of MmuPV1 were used as in situ hybridization probes for the detection of CRPV and MmuPV1 DNA in tissues respectively [15,37]. Counterstaining for ISH was Nuclear Fast Red (American MasterTech, Inc.) and for IHC was hematoxylin (Thomas Scientific).…”

“…This model has been in use in our laboratory for more than three decades. CRPV infections produce cutaneous tumours which, in time, progress to cancer [15]. Using this model, (1) We detected viral DNA in the blood of animals infected with CRPV; (2) We produced papillomavirus infections by injecting virus and viral DNA into the ear vein; and (3) We transfused blood containing CRPV virus from a previously transfused animal to an uninfected rabbit and demonstrated papilloma formation.…”

Gene Editing in Rabbits: Unique Opportunities for Translational Biomedical Research

“…Rabbits have long served as the gold standard model for the study of PV pathogenesis, as well as its associated diseases and cancers ( Cladel et al, 2019 ). Domestic rabbits are susceptible to infection by the cutaneous-tropic cottontail rabbit PV (CRPV) and the mucosal-tropic rabbit oral PV (ROPV) ( Christensen et al, 2000a , b , c ; Peh et al, 2002 ; Wilgenburg et al, 2005 ; Maglennon et al, 2011 ).…”

“…Domestic rabbits are susceptible to infection by the cutaneous-tropic cottontail rabbit PV (CRPV) and the mucosal-tropic rabbit oral PV (ROPV) ( Christensen et al, 2000a , b , c ; Peh et al, 2002 ; Wilgenburg et al, 2005 ; Maglennon et al, 2011 ). These preclinical models have proven valuable for understanding the pathogenesis of high-risk papillomavirus infection and cancer development ( Breitburd et al, 1997 ; Brandsma, 2005 ; Christensen et al, 2017 ), as well as played a pivotal role in the development of the two currently available prophylactic vaccines ( Breitburd et al, 1995 ; Christensen et al, 1996 ; Cladel et al, 2019 ). In addition, the rabbit model has been used widely to test anti-viral and anti-tumor therapies ( Christensen et al, 2000c , 2001 , 2014 ).…”