Model systems to study the life cycle of human papillomaviruses and HPV-associated cancers

Abstract

The prevalent human papillomaviruses (HPVs) infect either cutaneous or mucosal epithelium. Active Infections lead to epithelial hyperprolifeation and are usually cleared in healthy individuals within a year. Persistent infections in the anogenital tracts by certain high-risk genotypes such as HPV-16, HPV-18 and closely related types, can progress to high grade dysplasias and carcinomas in women and men, including cervical, vulva, penile and anal cancers. A significant fraction of the head and neck cancers are also caused by HPV-16. The viral oncogenes responsible for neoplastic conversion are E6 and E7 that disrupt the pathways controlled by the two major tumor suppressor genes, p53 and members of pRB family. Because HPV cannot be propagated in conventional submerged monolayer cell cultures, organotypic epithelial raft cultures that generate a stratified and differentiated epithelium have been used to study the viral life cycle. This article describes several systems to examine aspects of the viral productive phase, along with the advantages and limitations. Animal model systems of HPV carcinogenesis are also briefly described.

Functional Roles of E6 and E7 Oncoproteins in HPV-Induced Malignancies at Diverse Anatomical Sites

“…In this system either the spontaneously immortalized keratinocyte cell line Normal Immortal Keratinocytes (NIKS) or Human Foreskin Keratinocytes (HFKs) immortalized by telomerase are used to recapitulate the replicative viral life cycle [20]. NIKS are very effective in supporting the life cycle of a number of HR α-types such as HPV-16, -18, -31, -45 and -58, while the immortalized HFKs have been used to study the life cycle of some of the LR types such as HPV-11 [21,22,23].…”

Animal Models of Human Viral Diseases

“…Wild-type inbred mice cannot be used to study disease caused by papillomaviruses unless they are engrafted with relevant tissue, orthotopically transplanted or transgenic, but they are often used to look at immunogenicity of vaccines (Jagu et al, 2011;Oosterhuis et al, 2011). Transgenic mice used for HPV animal modeling typically express the viral oncogenes e5, e6, e7, or the entire early region of HPV-16 from the keratin 14 promoter which is only active in the basal cells of the mouse epithelium (Chow, 2015). Cancers in these models develop upon extended estrogen exposure (Maufort et al, 2010;Ocadiz-Delgado et al, 2009;stelzer et al, 2010;Thomas et al, 2011).…”

Three-dimensional cell culture models for investigating human viruses

“…Organotypic raft culture was originally designed to accurately mimic the in vivo morphological and physiological characteristic of the epidermis (Asselineau and Prunieras, 1984;Meyers et al, 1992). This system, forming a stratified and differentiated epithelium, has provided researchers a useful means to investigate epitheliotropic viruses (Chow, 2015). Over the past few years, human papillomavirus (HPV)-host interactions have been demonstrated with these raft cultures similar to those observed in vivo.…”