Lack of the canonical pRB-binding domain in the E7 ORF of artiodactyl papillomaviruses is associated with the development of fibropapillomas

Abstract

The L-X-C-X-E pRB-binding motif of papillomavirus (PV) E7 proteins has been implicated in the immortalization and transformation of the host cell. However, sequencing of the complete genomes of bovine papillomavirus type 3 (BPV-3), bovine papillomavirus type 5 (BPV-5), equine papillomavirus (EQPV) and reindeer (Rangifer tarandus) papillomavirus (RPV) supports the notion that the pRB-binding motif is not ubiquitous among E7 proteins in the PV proteome. Key among the animal groups that lack the pRB-binding domain are the artiodactyl PVs, including European elk PV (EEPV), deer PV (DPV), reindeer PV (RPV), ovine PVs types 1 and 2 (OvPV-1 and -2) and bovine PVs 1, 2 and 5 (BPV-1, -2 and -5). Whereas the presence of the pRB-binding domain is normally associated with papillomas, the artiodactyl PVs are marked by the development of fibropapillomas on infection. Previous studies emphasized the role of E5 in the pathogenic mechanism of fibropapilloma development, but correlation between the lack of an E7 pRB-binding domain and the unique pathology of the artiodactyl PVs suggests a more complicated mechanism and an early evolutionary divergence from a pRB-binding ancestor. INTRODUCTIONPapillomaviruses (PVs) are highly species-specific pathogens. They form a heterogeneous group of closed-circular, double-stranded DNA viruses measuring about 8 kb in size (Sundberg et al., 1996). Most PVs target the basal cells of dermal or mucosal epithelia (Cheville & Olson, 1964), and infection has been implicated in both benign and malignant lesions of epithelia in a broad range of animals (Sundberg & O'Banion, 1989). Though almost all known human PVs (HPVs) infect dermal or mucosal surfaces, in some animal PVs, most notably in the artiodactyl ruminant PVs, fibroblasts appear to be the primary target cells (Sundberg et al., 1985). However, regardless of species, infection generally manifests as a papilloma or fibropapilloma, and follows a cytopathic mechanism of cell proliferation (Sundberg et al., 1996). Historically, PVs had been classified according to their tissue tropism, and this grouping was supported by later phylogenetic analysis of PV sequence data (Chan et al., 1995;de Villiers, 2001;Myers, 1994). PV phylogenies typically subdivide into mucosal/genital HPVs, cutaneous EV HPVs and three main animal PV clades: the artiodactyl ruminant PVs, the distant avian PV group and a group containing canine, feline, rabbit and rodent PV types. However, sequence analysis has highlighted some significant exceptions. BPV-3, BPV-4 and BPV-6 do not group with the artiodactyl PVs, but instead form an isolated taxon (Jarrett et al., 1984), and HPV-1, HPV-41 and HPV-63 are most closely related to the canine and feline PVs, sharing little similarity to HPVs in either the mucosal or the cutaneous groups (Egawa et al., 1993).Although most work in the area has focused on HPVs, an ever-increasing number of animal PV isolates have been sequenced. These animal PVs share key clinical features of GenBank data deposited: bovine papillomavirus 3, AF486184; bo...

Overlapping reading frames in closely related human papillomaviruses result in modular rates of selection within E2

“…Overall, the small ratios of non-synonymous to synonymous changes and dN/dS values indicate that E1, L1 and L2 are under strong purifying selection, forming a functional core essential to the viral life cycle. Previously, we had also included E2 in this group because of its presence in all known PVs and its role in viral-genome replication (Narechania et al, 2004). However, in the current analysis, a remarkably consistent pattern of elevated non-synonymous E2 variation was observed, a pattern more in line with the values seen for the E6/E7 ORFs than the stable core E1, L1 and L2 ORFs.…”

Evolution of Linear Motifs within the Papillomavirus E7 Oncoprotein

“…On the other hand, the presence of fibropapillomas is associated with the absence of an Lx[CS] xE motif and the absence of an acidic stretch (Table 1). Our results confirm previous observations for the Lx[CS]xE motif in a smaller set of sequences 45 and strengthen the association of the Lx[CS]xE motif and the acidic stretch in functional and evolutionary terms. Last, we considered that mucosal human papillomavirus types differ in their oncogenic potential and can be classified as high risk or low risk.…”

“…9 Therefore, if appearance or disappearance of a particular linear motif was an adaptive event, one should expect to find variations in the E7 linear motif inventory that correlate with changes in phenotype. 45 …”

Rusa alfredi papillomavirus 1 – a novel deltapapillomavirus inducing endemic papillomatosis in the endangered Visayan spotted deer

“…This finding is typical for Delta-PV and other fibropapilloma-inducing PVs of the artiodactyls (Narechania et al, 2004) and is in agreement with the results of our histological examination. Due to the absence of leucine at amino acid position 278, two leucine zipper domains which were described for the other Delta-PV5 are absent in the RalPV1 E1.…”