Research Article: 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

Date Published: January 25, 2019

Publisher: Public Library of Science

Author(s): Eva-Maria Tombak, Andres Männik, Robert D. Burk, Roger Le Grand, Ene Ustav, Mart Ustav, Craig Meyers.


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.

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Human papillomaviruses (HPVs) are medically important pathogens that are responsible for a diverse range of epithelial manifestations ranging from asymptomatic infections to malignant neoplasia. Papillomaviruses are tissue-specific viruses that infect epithelial cells at different anatomic locations and can be transmitted through direct contact with infected tissue. HPVs are clustered phylogenetically into five (alpha, beta, gamma, mu and nu) genera, of which the alpha and beta viruses are the most extensively studied [1]. Beta HPVs (e.g., HPV5 and 8) target cutaneous epithelia, and their infections are usually asymptomatic in healthy individuals; however, in immunocompromised patients, these viruses have been suggested as etiological factors in the development of nonmelanoma skin cancer (NMSC) [2–5]. The members of the alpha genus infect mucosal epithelium and can be subdivided into high- and low-risk HPVs (HR-HPV and LR-HPV, respectively) based on their association with malignant progression [6]. Low-risk HPV types (e.g., HPV6 and HPV11) mainly cause genital warts, condylomas and papillomas that generally do not progress into malignant tumors [7]. In most instances, HR-HPV infections occur without any symptoms and are readily cleared by the immune system. Nevertheless, in some cases, HR-HPV (e.g., HPV16, 18, 31, 45) infections persist, causing genetic instability that can lead to the development of several anogenital (anal, penile, vulvar and vaginal) and head and neck cancers [8,9]. Cervical cancer is the fourth most common cancer among women worldwide; approximately half million new cases of malignant tumors are diagnosed each year, leading to death in approximately half of the cases [10]. The epidemic increase in HPV-positive oropharyngeal squamous cell carcinomas (OPSCC) has been reported recently–now up to 85% of the cases in the US and an even higher frequency in some European countries are HPV-positive [11–13]. Regardless of causing serious health problems and economic burden, there is still no approved effective cure for an ongoing HPV infection. Although there are approved invasive treatments removing the infected area in a quite extensive manner, such as cryogenic destruction, larger excision procedures, laser therapy and electrosurgery, these approaches do not eliminate HPV infection completely and therefore often lead to the necessity of repeated treatments (approximately a 40% chance of recurrence) [14,15]. Additionally, three efficacious prophylactic vaccines against HPV are available on the market: Gardasil (against types 6, 11, 16 and 18), Gardasil 9 (against types 16, 18, 31, 33, 45, 52, 58, 6 and 11) and Cervarix (against types 16 and 18); however, these vaccines target only nine of the most common HPV types and are restricted to those individuals who are naïve to certain HPV types [16,17]. Therefore, there is a great need for antiviral agents for treating ongoing HPV infections.

While cervical cancer is one of the leading causes of cancer mortality among women worldwide, no adequate animal models accurately mimicking PV infection in humans currently exist for testing the safety and efficacy of the compounds identified as HPV drug candidates. The genus Alphapapillomavirus is medically important, containing the oncogenic genital PV types being responsible for nearly all cases of human cervical cancer and a number of anal, penile, and head and neck carcinomas [8,9]. Alpha-PVs have also been identified in nonhuman primates, causing obvious clinical symptoms similar to PV-associated lesions observed in humans [1,21–25]. Different cynomolgus macaque PVs identified from the cervicovaginal area cluster within the alpha 12 species and show a close phylogenetic relationship with high-risk HPVs (e.g., HPV16) [1,23,25]. Additionally, a cutaneous type has been identified in severe papillomas on the hands and feet of a cynomolgus macaque, and it clustered with HPV5 into the genus β-PVs, to which all EV-type PVs belong [21]. Notably, similarities between specific MfPV and HPV types are detected at the sequence level and genome organization; however, all these findings have been reported based on sequence analyses [21,23].




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