Downloaded from www.microbiologyresearch.org by IP: 54.70.40.11 On: Thu, 03 Jan 2019 13:07:59 Macaca fascicularis papillomavirus type 1: a non- human primate betapapillomavirus causing rapidly progressive hand and foot papillomatosis Joongho Joh, 1 Kelly Hopper, 2 Koenraad Van Doorslaer, 3 John P. Sundberg, 4 Alfred B. Jenson 1 and Shin-Je Ghim 1 Correspondence Shin-Je Ghim sjghim01@louisville.edu 1 The James Graham Brown Cancer Center, The University of Louisville, Louisville, KY 40202, USA 2 The Mannheimer Foundation, Homestead, FL 33034-4102, USA 3 The Albert Einstein College of Medicine and The Albert Einstein Cancer Center, Bronx, NY 10461, USA 4 The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609-1500, USA Received 22 August 2008 Accepted 7 January 2009 Papillomaviruses (PVs) are a group of small, non-enveloped DNA viruses that cause mucosal or cutaneous neoplasia in a variety of animals. Whilst most papillomas will regress spontaneously, some may persist or undergo malignant transformation. In this study, aggressive, persistent and extensive warts were observed on the hands and feet of a cynomolgus macaque (Macaca fascicularis). The presence of PV in the wart biopsies was identified by immunohistochemistry and PCR amplification of PV DNA. The genomic DNA of this PV was cloned and sequenced, and the PV was designated M. fascicularis papillomavirus type 1 (MfPV-1). Its genome was 7588 bp in length and the organization of its putative open reading frames (E1, E2, E6, E7, L1, L2 and E4) was similar to that of other PVs. MfPV-1 had a short non-coding region (NCR) of 412 bp. Molecular analysis of MfPV-1 genomic DNA classified it into the genus Betapapillomavirus, to which all epidermodysplasia verruciformis (EV)-type PVs belong. Diseases caused by PVs of the genus Betapapillomavirus are usually associated with natural or iatrogenic immunosuppression. The genomic characterization performed in this study showed that MfPV-1 clustered within the genus Betapapillomavirus and also contained EV-type-specific motifs in its NCR. Further characterization of this virus and its host interactions may allow us to develop a non-human primate model for human betapapillomaviruses, a genus populated by human PV types causing EV. INTRODUCTION Papillomaviruses (PVs) infect cutaneous and mucosal epithelial cells and cause both benign and malignant hyperproliferative lesions (Chang et al., 1990; Jenson et al., 2001; Howley & Lowy, 2007). PVs are ubiquitous and have been identified as infectious agents in birds and mammals (Sundberg & Reichmann, 1993). Of the nearly 100 types of human PV (HPV) sequenced so far (de Villiers et al., 2004; Howley & Lowy, 2007), approximately 40 % are mucoso- trophic, with the rest infecting the skin. PVs are a group of small, naked, icosahedral viruses with a double-stranded DNA genome of 7–8 kb. Despite their highly conserved genomic organization, each PV type is species- and tissue- specific. Whilst initial PV infection occurs at the basal cell layer of the epithelium, the maturation of new viruses occurs at the surface of the epithelium, where PV capsid proteins are abundantly expressed. This occurs in koilo- cytotic cells, which display the cytopathic effects of PV infection, express large amounts of capsid proteins and are only observed on the surface of fully developed warts (Howley & Lowy, 2007). Because PVs cannot be replicated in conventional cell culture and infectious transmission of PVs between species has not been reported, an ideal animal model for HPVs of the genus Betapapillomavirus has yet to be developed. HPVs may be causally linked to as many as 99.7 % of cervical cancers and are also involved in head and neck cancers (Psyrri & DiMaio, 2008) and lung cancers (Hajdu & Ali, 2008). The family Papillomaviridae consists of at least 18 separate genera, three of which (Alpha-, Beta- and Gammapapillo- mavirus) contain 80 % of all known PVs and are entirely composed of primate PVs. Alphapapillomaviruses (a-PVs) are found in mucosal and cutaneous lesions in humans and primates, whereas betapapillomaviruses (b-PVs) and The GenBank/EMBL/DDBJ accession number for the MfPV-1 genome sequence determined in this study is EF028290. Journal of General Virology (2009), 90, 987–994 DOI 10.1099/vir.0.006544-0 006544 G 2009 SGM Printed in Great Britain 987