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Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan


Genital human papillomavirus (HPV) infection is the most common sexually transmitted infection, and virtually all cases of cervical cancer are attributable to infection by a subset of HPVs (reviewed in ref. 1). Despite the high incidence of HPV infection and the recent development of a prophylactic vaccine that confers protection against some HPV types2, many features of HPV infection are poorly understood. It remains worthwhile to consider other interventions against genital HPVs, particularly those that target infections not prevented by the current vaccine. However, productive papillomavirus infection is species- and tissue-restricted, and traditional models use animal papillomaviruses that infect the skin or oral mucosa3. Here we report the development of a mouse model of cervicovaginal infection with HPV16 that recapitulates the establishment phase of papillomavirus infection. Transduction of a reporter gene by an HPV16 pseudovirus was characterized by histology and quantified by whole-organ, multispectral imaging. Disruption of the integrity of the stratified or columnar genital epithelium was required for infection, which occurred after deposition of the virus on the basement membrane underlying basal keratinocytes. A widely used vaginal spermicide, nonoxynol-9 (N-9), greatly increased susceptibility to infection. In contrast, carrageenan, a polysaccharide present in some vaginal lubricants, prevented infection even in the presence of N-9, suggesting that carrageenan might serve as an effective topical HPV microbicide.

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Figure 1: Quantitative analysis of murine reproductive tract infection.
Figure 2: Effects of mechanical disruption, N-9 and carrageenan on HPV16 pseudovirus infection of the mouse cervicovaginal mucosa.
Figure 3: HPV16-RFP pseudovirus trafficking and infection in the vaginal stratified squamous epithelium as visualized in genital tissue sections by indirect immunofluorescence microscopy.
Figure 4: Alexa Fluor 488–conjugated HPV16-RFP pseudovirus trafficking and infection in the columnar epithelium of the cervical transformation zone as visualized in genital tissue sections by direct fluorescence microscopy.


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This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We thank S.H. Yuspa and other members of the In Vitro Pathogenesis section of the Laboratory of Cancer Biology and Genetics at the US National Cancer Institute for technical assistance and guidance with antibody selection and tissue staining.

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Correspondence to John T Schiller.

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Supplementary information

Supplementary Fig. 1

Systemic hormonal pretreatment before pseudovirus challenge. (PDF 59 kb)

Supplementary Fig. 2

Typical confocal microscopic appearance of the cervicovaginal epithelium after pseudovirus challenge. (PDF 268 kb)

Supplementary Fig. 3

Pseudovirus reporter gene expression over time. (PDF 35 kb)

Supplementary Fig. 4

Target cell identification with anti-keratin6 antibody staining. (PDF 320 kb)

Supplementary Fig. 5

Requirement of L2 for infection of the genital epithelium. (PDF 33 kb)

Supplementary Fig. 6

Virus-like particle (VLP) immunization protects against type-specific pseudovirus challenge. (PDF 41 kb)

Supplementary Fig. 7

Basement membrane staining of laminin-5. (PDF 72 kb)

Supplementary Table 1

Performance of reporter constructs in mouse challenge model. (PDF 26 kb)

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Roberts, J., Buck, C., Thompson, C. et al. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nat Med 13, 857–861 (2007).

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