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

Nature Medicine volume 13, pages 857–861 (2007)Cite this article

Abstract

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.

References

  1. Trottier, H. & Franco, E.L. The epidemiology of genital human papillomavirus infection. Vaccine (2005).

  2. Lowy, D.R. & Schiller, J.T. Prophylactic human papillomavirus vaccines. J. Clin. Invest. 116, 1167–1173 (2006).

    Article  CAS  Google Scholar 

  3. Campo, M.S. Animal models of papillomavirus pathogenesis. Virus Res. 89, 249–261 (2002).

    Article  CAS  Google Scholar 

  4. Buck, C.B., Pastrana, D.V., Lowy, D.R. & Schiller, J.T. Efficient intracellular assembly of papillomaviral vectors. J. Virol. 78, 751–757 (2004).

    Article  CAS  Google Scholar 

  5. Buck, C.B., Thompson, C.D., Pang, Y.Y., Lowy, D.R. & Schiller, J.T. Maturation of papillomavirus capsids. J. Virol. 79, 2839–2846 (2005).

    Article  CAS  Google Scholar 

  6. Richards, R.M., Lowy, D.R., Schiller, J.T. & Day, P.M. Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection. Proc. Natl. Acad. Sci. USA 103, 1522–1527 (2006).

    Article  CAS  Google Scholar 

  7. Pastrana, D.V. et al. Reactivity of human sera in a sensitive, high-throughput pseudovirus-based papillomavirus neutralization assay for HPV16 and HPV18. Virology 321, 205–216 (2004).

    Article  CAS  Google Scholar 

  8. Pyeon, D., Lambert, P.F. & Ahlquist, P. Production of infectious human papillomavirus independently of viral replication and epithelial cell differentiation. Proc. Natl. Acad. Sci. USA 102, 9311–9316 (2005).

    Article  CAS  Google Scholar 

  9. Buck, C.B. et al. Carrageenan is a potent inhibitor of papillomavirus infection. PLoS Pathog. 2, e69 (2006).

    Article  Google Scholar 

  10. Pastrana, D.V. et al. Cross-neutralization of cutaneous and mucosal Papillomavirus types with anti-sera to the amino terminus of L2. Virology 337, 365–372 (2005).

    Article  CAS  Google Scholar 

  11. Reuter, J.D., Gomez, D., Brandsma, J.L., Rose, J.K. & Roberts, A. Optimization of cottontail rabbit papilloma virus challenge technique. J. Virol. Methods 98, 127–134 (2001).

    Article  CAS  Google Scholar 

  12. Shaner, N.C. et al. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat. Biotechnol. 22, 1567–1572 (2004).

    Article  CAS  Google Scholar 

  13. Roberts, J.N. et al. Infection of murine vaginal or endocervical mucosa with human papillomavirus pseudovirions. Nat. Protoc. published online July 2007 (doi:10.1038/nprot.2007.235).

  14. Gimenez-Conti, I.B. et al. Expression of keratins in mouse vaginal epithelium. Differentiation 56, 143–151 (1994).

    Article  CAS  Google Scholar 

  15. Roden, R.B. et al. Positively charged termini of the L2 minor capsid protein are necessary for papillomavirus infection. J. Virol. 75, 10493–10497 (2001).

    Article  CAS  Google Scholar 

  16. Kirnbauer, R., Booy, F., Cheng, N., Lowy, D.R. & Schiller, J.T. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc. Natl. Acad. Sci. USA 89, 12180–12184 (1992).

    Article  CAS  Google Scholar 

  17. Koutsky, L.A. et al. A controlled trial of a human papillomavirus type 16 vaccine. N. Engl. J. Med. 347, 1645–1651 (2002).

    Article  CAS  Google Scholar 

  18. Harper, D.M. et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 364, 1757–1765 (2004).

    Article  CAS  Google Scholar 

  19. Niruthisard, S., Roddy, R.E. & Chutivongse, S. The effects of frequent nonoxynol-9 use on the vaginal and cervical mucosa. Sex Transm. Dis. 18, 176–179 (1991).

    Article  CAS  Google Scholar 

  20. Patton, D.L., Kidder, G.G., Sweeney, Y.C., Rabe, L.K. & Hillier, S.L. Effects of multiple applications of benzalkonium chloride and nonoxynol 9 on the vaginal epithelium in the pigtailed macaque (Macaca nemestrina). Am. J. Obstet. Gynecol. 180, 1080–1087 (1999).

    Article  CAS  Google Scholar 

  21. Culp, T.D., Budgeon, L.R., Marinkovich, M.P., Meneguzzi, G. & Christensen, N.D. Keratinocyte-secreted laminin 5 can function as a transient receptor for human papillomaviruses by binding virions and transferring them to adjacent cells. J. Virol. 80, 8940–8950 (2006).

    Article  CAS  Google Scholar 

  22. Wilkinson, D., Tholandi, M., Ramjee, G. & Rutherford, G.W. Nonoxynol-9 spermicide for prevention of vaginally acquired HIV and other sexually transmitted infections: systematic review and meta-analysis of randomised controlled trials including more than 5000 women. Lancet Infect. Dis. 2, 613–617 (2002).

    Article  CAS  Google Scholar 

  23. Hermonat, P.L., Daniel, R.W. & Shah, K.V. The spermicide nonoxynol-9 does not inactivate papillomavirus. Sex. Transm. Dis. 19, 203–205 (1992).

    Article  CAS  Google Scholar 

  24. Coggins, C. et al. Preliminary safety and acceptability of a carrageenan gel for possible use as a vaginal microbicide. Sex. Transm. Infect. 76, 480–483 (2000).

    Article  CAS  Google Scholar 

  25. Spieler, R. Seaweed compound's anti-HIV efficacy will be tested in southern Africa. Lancet 359, 1675 (2002).

    Article  Google Scholar 

  26. Maguire, R.A., Zacharopoulos, V.R. & Phillips, D.M. Carrageenan-based nonoxynol-9 spermicides for prevention of sexually transmitted infections. Sex. Transm. Dis. 25, 494–500 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

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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Authors and Affiliations

  1. Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892-4263, Maryland, USA

    Jeffrey N Roberts, Christopher B Buck, Cynthia D Thompson, Rhonda Kines, Douglas R Lowy & John T Schiller

  2. Science Applications International Corporation (SAIC)-Frederick, Frederick, 21702, Maryland, USA

    Marcelino Bernardo

  3. Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892-1088, Maryland, USA

    Peter L Choyke

Authors
  1. Jeffrey N Roberts
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  6. Peter L Choyke
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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). https://doi.org/10.1038/nm1598

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