The molecular biology and HPV drug responsiveness of cynomolgus macaque papillomaviruses support their use in the development of a relevant in vivo model for antiviral drug testing.

Eva-Maria Tombak,Roger Le Grand,Andres Männik,Ene Ustav,Mart Ustav,Robert D Burk,Craig Meyers

doi:10.1371/journal.pone.0211235

Abstract

Due to the extreme tissue and species restriction of the papillomaviruses (PVs), there is a great need for animal models that accurately mimic PV infection in humans for testing therapeutic strategies against human papillomaviruses (HPVs). In this study, we present data that demonstrate that in terms of gene expression during initial viral DNA amplification, Macaca fascicularis PV (MfPV) types 5 and 8 appear to be similar to mucosal oncogenic HPVs, while MfPV1 (isolated from skin) resembles most high-risk cutaneous beta HPVs (HPV5). Similarities were also observed in replication properties during the initial amplification phase of the MfPV genomes. We demonstrate that high-risk mucosal HPV-specific inhibitors target the transient replication of the MfPV8 genomes, which indicates that similar pathways are used by the high-risk HPVs and MfPVs during their genome replication. Taking all into account, we propose that Macaca fascicularis may serve as a highly relevant model for preclinical tests designed to evaluate therapeutic strategies against HPV-associated lesions.

Highlights

The molecular biology of cynomolgus macaque PVs support their use in the development of a in vivo model replication in the U2OS cell line (Fig 1), it implies that Macaca fascicularis PV (MfPV) genomes are transcriptionally active in these cells, providing the tool for experimental description of the viral transcriptomes
The molecular biology of cynomolgus macaque PVs support their use in the development of a in vivo model homologous to preferred early cleavage sites (CSs) identified in HPV5 [29,30,35]
The molecular biology of cynomolgus macaque PVs support their use in the development of a in vivo model cluster within the alpha 12 species and show a close phylogenetic relationship with high-risk Human papillomaviruses (HPVs) (e.g., HPV16) [1,23,25]

Summary

Introduction

Human papillomaviruses (HPVs) are medically important pathogens that are responsible for a diverse range of epithelial manifestations ranging from asymptomatic infections to malignant. The funder provided support in the form of salaries for authors [MU, EMT, AM], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section

Methods

Results

Conclusion