J Virol. 2013 Aug;87(16):9391-5.

Secondary infections, expanded tissue tropism, and evidence for malignant potential in immunocompromised mice infected with Mus musculus papillomavirus 1 DNA and virus.

Cladel NM, Budgeon LR, Cooper TK, Balogh KK, Hu J, Christensen ND.

Jake Gittlen Cancer Research Foundation, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.

 

ABSTRACT

Papillomavirus disease poses a special challenge to people with compromised immune systems. Appropriate models to study infections in these individuals are lacking. We report here the development of a model that will help to address these deficiencies. The MmuPV1 genome was synthesized and used successfully to produce virus from DNA infections in immunocompromised mice. In these early studies, we have demonstrated both primary and secondary infections, expanded tissue tropism, and extensive dysplasia.

PMID: 23785210

 

SUPPLEMENT:

Disease resulting from human papillomaviruses (HPVs) remains a significant challenge despite the availability of two protective vaccines to prevent infections by a subset of HPV types.  Nearly all cases of cervical cancer can be linked to papillomavirus infection,  and HPVs are also implicated in a subset of head and neck and skin cancers.  No effective therapeutic intervention is available to eradicate existing infections. Cervical cancer remains one of the leading causes of death in women in the developing world.

One of the challenges for papillomavirus research has been the lack of a suitable animal model.  The virus cannot be grown in cell culture, as it requires differentiating cells for the completion of the life cycle.  A rodent model has long been sought but only recently has a laboratory mouse papillomavirus been reported (Ingle et al. Veterinary Pathology 48(2) 500-505, 2011).  This virus, now termed MmuPV1, was found in a colony of NMRI Foxn1nu/Foxn1 numice in India and was reported to be “strictly cutaneous” in its tropism.

In the paper of Cladel, et. al, referenced here, we discuss the synthesis of the MmuPV1  viral genome and its use to generate infectious virus in Foxn1nu/Foxn1numice.  We report the observation of primary infections on back sites as well as multiple secondary infections, some of which were observed at mucosal sites.

Work with this model is ongoing. We have utilized quasivirus technology, originally pioneered in this laboratory (Culp, et. al, JV, Nov 2006, 11381-11384)), and have generated infections on both the tail and at the muco-cutaneous junction on the face with this these infectious virus-like constructs.  Photos are shown below to illustrate this work.  In the near future we will report our findings on primary mucosal infections with MmuPV1.

We expect this work to lead to a better understanding of the role of papillomaviruses in malignant progression.  Histological analysis has confirmed dysplasias in several tissues and studies of the malignant potential of the virus are on- going.  The model will also be useful to study factors underlying tissue tropism.  Unlike most papillomaviruses, MmuPV1 exhibits a broader tissue tropism, an unexpected and interesting finding.  The model will also be valuable for the testing of potential therapeutic agents and interventions.

fig1Fig1. Developing papillomas on a Foxn1nu/Foxn1nu mouse tail.  Papillomas were initiated with quasivirus consisting of an HPV31 capsid and the MmuPV1 genome.  Photo was taken five weeks post infection.

 

fig2Fig2. Facial lesions on a Foxn1nu/Foxn1nu mouse.  Papillomas were initiated with quasivirus consisting of an HPV31 capsid and MmuPV1 genome.  Photo was taken five weeks post infection.

 

fig3Fig3. Tail lesions on a Foxn1nu/Foxn1nu mouse tail.  Infection was generated with wild type virus.  Photo was taken 10 weeks post infection.

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