Contents lists available at ScienceDirect Papillomavirus Research journal homepage: www.elsevier.com/locate/pvr Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions Z.K. Tuong, K. Noske, P. Kuo, A.A. Bashaw, S.M. Teoh, I.H. Frazer ⁎ The University of Queensland, Faculty of Medicine, Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia ABSTRACT Currently available vaccines prevent HPV infection and development of HPV-associated malignancies, but do not cure existing HPV infections and dysplastic lesions. Persistence of infection(s) in immunocompetent patients may reflect induction of local immunosuppressive mechanisms by HPV, providing a target for therapeutic inter- vention. We have proposed that a mouse, expressing HPV16 E7 oncoprotein under a Keratin 14 promoter (K14E7 mice), and which develops epithelial hyperplasia, may assist with understanding local immune suppression mechanisms that support persistence of HPV oncogene-induced epithelial hyperplasia. K14E7 skin grafts recruit immune cells from immunocompetent hosts, but consistently fail to be rejected. Here, we review the literature on HPV-associated local immunoregulation, and compare the findings with published observations on the K14E7 transgenic murine model, including comparison of the transcriptome of human HPV-infected pre-malignancies with that of murine K14E7 transgenic skin. We argue from the similarity of i) the literature findings and ii) the transcriptome profiles that murine K14E7 transgenic skin recapitulates the cellular and secreted protein profiles of high-grade HPV-associated lesions in human subjects. We propose that the K14E7 mouse may be an appro- priate model to further study the immunoregulatory effects of HPV E7 expression, and can facilitate develop- ment and testing of therapeutic vaccines. 1. Introduction Cervical cancer is responsible for 5% of the global cancer burden and it is the second most diagnosed cancer in women [1]. Cervical and other anogenital cancers are typically associated with infection by a subset of human papillomaviruses (HPVs). The ‘high-risk’ oncogenic HPV genotypes 16 and 18 are responsible for about 70% of all cervical cancer cases worldwide and approximately 50% of the cervical cancers are caused by HPV16 [2,3]. Prevention of infection by high-risk onco- genic HPVs (HPV16 and 18) has been effective (~95%) with the de- velopment of virus-like particle-based vaccines [4]. Currently, there are three approved multi-valent (Gardasil® and Gardasil® 9, Merck) and bivalent (Cervarix®, GlaxoSmithKline) commercially available effica- cious vaccines. However, the adoption of these vaccines in resource- limited countries has been hindered by high costs of the vaccines, jeopardising the prevention of HPV infection despite proven clinical efficacy [1,5]. Furthermore, current vaccines do not protect against existing infections, offer an undetermined capacity in maintaining protection over time and will not have a major impact on cancer incidence for at least another 30 years. Thus, it remains a research priority to discover improved therapies that can resolve HPV-associated disease in patients who do not benefit from currently available vac- cines. HPVs are epitheliotropic double-stranded DNA viruses that infect the basal keratinocytes on surface epithelia of skin and mucous mem- branes. Replication of virus is dependent on the expression of non- structural viral genes E1, E2, E6, E7 and the structural L1 and L2 capsid proteins. The E1 and E2 proteins regulate viral DNA replication, while E6 and E7 deregulate cell cycle control and promote epithelial pro- liferation and delay epithelial differentiation. The late structural viral proteins L1 and L2 are responsible for virion assembly and lytic release and form the basis of currently available prophylactic vaccine for- mulations. Most HPV infections are cleared rapidly by the immune system, but extended virus persistence increases the risk of progressive dysplastic transformation of normal epithelium, eventually into cancer [6]. The clinical stages of cervical pre-malignancy are classified into worsening grades of dysplasia (cervical intraepithelial neoplasia (CIN) grades 1, 2, and 3; CIN1, CIN2, CIN3). CIN1/2 lesions frequently https://doi.org/10.1016/j.pvr.2017.10.001 Received 1 August 2017; Received in revised form 14 October 2017; Accepted 16 October 2017 ⁎ Correspondence to: The University of Queensland, Faculty of Medicine, Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, 37 Kent Street, Woolloongabba, QLD 4102, Australia. E-mail address: i.frazer@uq.edu.au (I.H. Frazer). Papillomavirus Research 5 (2018) 6–20 Available online 19 October 2017 2405-8521/ © 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). T