1887

Abstract

Noninvasive and practical techniques to longitudinally track viral infection are sought after in clinical practice. We report a proof-of-principle study to monitor the viral DNA copy number using a newly established mouse papillomavirus (MmuPV1) mucosal infection model. We hypothesized that viral presence could be identified and quantified by collecting lavage samples from cervicovaginal, anal and oral sites. Nude mice infected at these sites with infectious MmuPV1 were tracked for up to 23 weeks starting at 6 weeks post-infection. Viral DNA copy number was determined by SYBR Green Q-PCR analysis. In addition, we tracked viral DNA load through three complete oestrous cycles to pinpoint whether there was a correlation between the DNA load and the four stages of the oestrous cycle. Our results showed that high viral DNA copy number was reproducibly detected from both anal and cervicovaginal lavage samples. The infection and disease progression were further confirmed by histology, cytology, hybridization, immunohistochemistry and transmission electron microscopy. Interestingly, the viral copy number fluctuated over the oestrous cycle, with the highest level at the oestrus stage, implying that multiple sampling might be necessary to provide a reliable diagnosis. Virus DNA was detected in oral lavage samples at a later time after infection. Lower viral DNA load was found in oral samples when compared with those in anal and vaginal tracts. To our knowledge, our study is the first study to sequentially monitor papillomavirus infection from mucosal anal, oral and vaginal tracts in a preclinical model.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000295
2015-12-01
2019-10-15
Loading full text...

Full text loading...

/deliver/fulltext/jgv/96/12/3554.html?itemId=/content/journal/jgv/10.1099/jgv.0.000295&mimeType=html&fmt=ahah

References

  1. Assi R. , Reddy V. , Einarsdottir H. , Longo W. E. . ( 2014;). Anorectal human papillomavirus: current concepts. Yale J Biol Med 87: 537–547 [PubMed].
    [Google Scholar]
  2. Baandrup L. , Thomsen L. T. , Olesen T. B. , Andersen K. K. , Norrild B. , Kjaer S. K. . ( 2014;). The prevalence of human papillomavirus in colorectal adenomas and adenocarcinomas: a systematic review and meta-analysis. Eur J Cancer 50: 1446–1461 [CrossRef] [PubMed].
    [Google Scholar]
  3. Bergot A. S. , Kassianos A. , Frazer I. H. , Mittal D. . ( 2011;). New approaches to immunotherapy for HPV associated cancers. Cancers (Basel) 3: 3461–3495 [CrossRef] [PubMed].
    [Google Scholar]
  4. Boutaga K. , Savelkoul P. H. , Winkel E. G. , van Winkelhoff A. J. . ( 2007;). Comparison of subgingival bacterial sampling with oral lavage for detection and quantification of periodontal pathogens by real-time polymerase chain reaction. J Periodontol 78: 79–86 [CrossRef] [PubMed].
    [Google Scholar]
  5. Bown E. , Shah V. , Sridhar T. , Boyle K. , Hemingway D. , Yeung J. M. . ( 2014;). Cancers of the anal canal: diagnosis, treatment and future strategies. Future Oncol 10: 1427–1441 [CrossRef] [PubMed].
    [Google Scholar]
  6. Brandsma J. L. . ( 2005;). The cottontail rabbit papillomavirus model of high-risk HPV-induced disease. Methods Mol Med 119: 217–235 [PubMed].
    [Google Scholar]
  7. Brickman C. , Palefsky J. M. . ( 2015;). Human papillomavirus in the HIV-infected host: epidemiology and pathogenesis in the antiretroviral era. Curr HIV/AIDS Rep 12: 6–15 [CrossRef] [PubMed].
    [Google Scholar]
  8. Byers S. L. , Wiles M. V. , Dunn S. L. , Taft R. A. . ( 2012;). Mouse estrous cycle identification tool and images. PLoS One 7: e35538 [CrossRef] [PubMed].
    [Google Scholar]
  9. Caligioni C. S. . ( 2009;). Assessing reproductive status/stages in mice. Curr Protoc Neurosci 48: A.4I.1–A.4I.8.
    [Google Scholar]
  10. Campo M. S. . ( 2002;). Animal models of papillomavirus pathogenesis. Virus Res 89: 249–261 [CrossRef] [PubMed].
    [Google Scholar]
  11. Campo M. S. , Roden R. B. . ( 2010;). Papillomavirus prophylactic vaccines: established successes, new approaches. J Virol 84: 1214–1220 [CrossRef] [PubMed].
    [Google Scholar]
  12. Castell S. , Krause G. , Schmitt M. , Pawlita M. , Deleré Y. , Obi N. , Flesch-Janys D. , Kemmling Y. , Kaufmann A. M. . ( 2014;). Feasibility and acceptance of cervicovaginal self-sampling within the German National Cohort (Pretest 2). Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 57: 1270–1276 [CrossRef] [PubMed].
    [Google Scholar]
  13. Cladel N. M. , Hu J. , Balogh K. , Mejia A. , Christensen N. D. . ( 2008;). Wounding prior to challenge substantially improves infectivity of cottontail rabbit papillomavirus and allows for standardization of infection. J Virol Methods 148: 34–39 [CrossRef] [PubMed].
    [Google Scholar]
  14. Cladel N. M. , Budgeon L. R. , Cooper T. K. , Balogh K. K. , Hu J. , Christensen N. D. . ( 2013;). Secondary infections, expanded tissue tropism, and evidence for malignant potential in immunocompromised mice infected with Mus musculus papillomavirus 1 DNA and virus. J Virol 87: 9391–9395 [CrossRef] [PubMed].
    [Google Scholar]
  15. Cladel N. M. , Budgeon L. R. , Balogh K. K. , Cooper T. K. , Hu J. , Christensen N. D. . ( 2015;). A novel pre-clinical murine model to study the life cycle and progression of cervical and anal papillomavirus infections. PLoS One 10: e0120128 [CrossRef] [PubMed].
    [Google Scholar]
  16. Cui X. , Yu S. , Tamhane A. , Causey Z. L. , Steg A. , Danila M. I. , Reynolds R. J. , Wang J. , Wanzeck K. C. , other authors . ( 2015;). Simple regression for correcting DeltaCt bias in RT-qPCR low-density array data normalization. BMC Genomics 16: 82 [CrossRef].
    [Google Scholar]
  17. Curlin M. E. , Leelawiwat W. , Dunne E. F. , Chonwattana W. , Mock P. A. , Mueanpai F. , Thep-Amnuay S. , Whitehead S. J. , McNicholl J. M. . ( 2013;). Cyclic changes in HIV shedding from the female genital tract during the menstrual cycle. J Infect Dis 207: 1616–1620 [CrossRef] [PubMed].
    [Google Scholar]
  18. Deleré Y. , Schuster M. , Vartazarowa E. , Hänsel T. , Hagemann I. , Borchardt S. , Perlitz H. , Schneider A. , Reiter S. , Kaufmann A. M. . ( 2011;). Cervicovaginal self-sampling is a reliable method for determination of prevalence of human papillomavirus genotypes in women aged 20 to 30 years. J Clin Microbiol 49: 3519–3522 [CrossRef] [PubMed].
    [Google Scholar]
  19. Dochez C. , Bogers J. J. , Verhelst R. , Rees H. . ( 2014;). HPV vaccines to prevent cervical cancer and genital warts: an update. Vaccine 32: 1595–1601 [CrossRef] [PubMed].
    [Google Scholar]
  20. Doorbar J. . ( 2013;). Latent papillomavirus infections and their regulation. Curr Opin Virol 3: 416–421 [CrossRef] [PubMed].
    [Google Scholar]
  21. Forslund O. , Johansson H. , Madsen K. G. , Kofoed K. . ( 2013;). The nasal mucosa contains a large spectrum of human papillomavirus types from the Betapapillomavirus and Gammapapillomavirus genera. J Infect Dis 208: 1335–1341 [CrossRef] [PubMed].
    [Google Scholar]
  22. Gallichan W. S. , Rosenthal K. L. . ( 1996;). Effects of the estrous cycle on local humoral immune responses and protection of intranasally immunized female mice against herpes simplex virus type 2 infection in the genital tract. Virology 224: 487–497 [CrossRef] [PubMed].
    [Google Scholar]
  23. García-Sastre A. , Durbin R. K. , Zheng H. , Palese P. , Gertner R. , Levy D. E. , Durbin J. E. . ( 1998;). The role of interferon in influenza virus tissue tropism. J Virol 72: 8550–8558 [PubMed].
    [Google Scholar]
  24. Gill H. S. , Prausnitz M. R. . ( 2008;). Pocketed microneedles for drug delivery to the skin. J Phys Chem Solids 69: 1537–1541 [CrossRef] [PubMed].
    [Google Scholar]
  25. Gill H. S. , Denson D. D. , Burris B. A. , Prausnitz M. R. . ( 2008;). Effect of microneedle design on pain in human volunteers. Clin J Pain 24: 585–594 [CrossRef] [PubMed].
    [Google Scholar]
  26. Haguenoer K. , Sengchanh S. , Gaudy-Graffin C. , Boyard J. , Fontenay R. , Marret H. , Goudeau A. , Pigneaux de Laroche N. , Rusch E. , Giraudeau B. . ( 2014;). Vaginal self-sampling is a cost-effective way to increase participation in a cervical cancer screening programme: a randomised trial. Br J Cancer 111: 2187–2196 [CrossRef] [PubMed].
    [Google Scholar]
  27. Handisurya A. , Day P. M. , Thompson C. D. , Bonelli M. , Lowy D. R. , Schiller J. T. . ( 2014;). Strain-specific properties and T cells regulate the susceptibility to papilloma induction by Mus musculus papillomavirus 1. PLoS Pathog 10: e1004314 [CrossRef] [PubMed].
    [Google Scholar]
  28. Holmgren S. C. , Patterson N. A. , Ozbun M. A. , Lambert P. F. . ( 2005;). The minor capsid protein L2 contributes to two steps in the human papillomavirus type 31 life cycle. J Virol 79: 3938–3948 [CrossRef] [PubMed].
    [Google Scholar]
  29. Hu J. , Cladel N. M. , Balogh K. , Budgeon L. , Christensen N. D. . ( 2007;). Impact of genetic changes to the CRPV genome and their application to the study of pathogenesis in vivo. Virology 358: 384–390 [CrossRef] [PubMed].
    [Google Scholar]
  30. Hu J. , Cladel N. M. , Budgeon L. , Balogh K. K. , Christensen N. D. , Papillomavirus D. N. A. . ( 2009;). Papillomavirus DNA complementation in vivo. Virus Res 144: 117–122 [CrossRef] [PubMed].
    [Google Scholar]
  31. Igidbashian S. , Boveri S. , Spolti N. , Radice D. , Sandri M. T. , Sideri M. . ( 2011;). Self-collected human papillomavirus testing acceptability: comparison of two self-sampling modalities. J Womens Health (Larchmt) 20: 397–402 [CrossRef] [PubMed].
    [Google Scholar]
  32. Joh J. , Jenson A. B. , Proctor M. , Ingle A. , Silva K. A. , Potter C. S. , Sundberg J. P. , Ghim S. J. . ( 2012;). Molecular diagnosis of a laboratory mouse papillomavirus (MusPV). Exp Mol Pathol 93: 416–421 [CrossRef] [PubMed].
    [Google Scholar]
  33. Kaushic C. , Ashkar A. A. , Reid L. A. , Rosenthal K. L. . ( 2003;). Progesterone increases susceptibility and decreases immune responses to genital herpes infection. J Virol 77: 4558–4565 [CrossRef] [PubMed].
    [Google Scholar]
  34. Kaushic C. , Roth K. L. , Anipindi V. , Xiu F. . ( 2011;). Increased prevalence of sexually transmitted viral infections in women: the role of female sex hormones in regulating susceptibility and immune responses. J Reprod Immunol 88: 204–209 [CrossRef] [PubMed].
    [Google Scholar]
  35. Korn A. P. . ( 1996;). Interpretation of abnormal Pap smears. Infect Med 13: 405–406.
    [Google Scholar]
  36. Lampinen T. M. , Latulippe L. , van Niekerk D. , Schilder A. J. , Miller M. L. , Anema A. , Hogg R. S. . ( 2006;). Illustrated instructions for self-collection of anorectal swab specimens and their adequacy for cytological examination. Sex Transm Dis 33: 386–388 [CrossRef] [PubMed].
    [Google Scholar]
  37. Larionov A. , Krause A. , Miller W. . ( 2005;). A standard curve based method for relative real time PCR data processing. BMC Bioinformatics 6: 62 [CrossRef] [PubMed].
    [Google Scholar]
  38. Liszewski W. , Ananth A. T. , Ploch L. E. , Rogers N. E. . ( 2014;). Anal Pap smears and anal cancer: what dermatologists should know. J Am Acad Dermatol 71: 985–992 [CrossRef] [PubMed].
    [Google Scholar]
  39. Liu S. H. , Brotman R. M. , Zenilman J. M. , Gravitt P. E. , Cummings D. A. . ( 2013;). Menstrual cycle and detectable human papillomavirus in reproductive-age women: a time series study. J Infect Dis 208: 1404–1415 [CrossRef] [PubMed].
    [Google Scholar]
  40. Liu S. H. , Cummings D. A. , Zenilman J. M. , Gravitt P. E. , Brotman R. M. . ( 2014;). Characterizing the temporal dynamics of human papillomavirus DNA detectability using short-interval sampling. Cancer Epidemiol Biomarkers Prev 23: 200–208 [CrossRef] [PubMed].
    [Google Scholar]
  41. Massad L. S. , Xie X. , Burk R. , Keller M. J. , Minkoff H. , D'Souza G. , Watts D. H. , Palefsky J. , Young M. , other authors . ( 2014;). Long-term cumulative detection of human papillomavirus among HIV seropositive women. AIDS 28: 2601–2608 [CrossRef] [PubMed].
    [Google Scholar]
  42. McFadden G. , Mohamed M. R. , Rahman M. M. , Bartee E. . ( 2009;). Cytokine determinants of viral tropism. Nat Rev Immunol 9: 645–655 [CrossRef] [PubMed].
    [Google Scholar]
  43. McLean A. C. , Valenzuela N. , Fai S. , Bennett S. A. . ( 2012;). Performing vaginal lavage, crystal violet staining, and vaginal cytological evaluation for mouse estrous cycle staging identification. J Vis Exp 15: e4389 [PubMed].
    [Google Scholar]
  44. Medeiros L. R. , Ethur A. B. , Hilgert J. B. , Zanini R. R. , Berwanger O. , Bozzetti M. C. , Mylius L. C. . ( 2005;). Vertical transmission of the human papillomavirus: a systematic quantitative review. Cad Saude Publica 21: 1006–1015 [CrossRef] [PubMed].
    [Google Scholar]
  45. Meyer M. F. , Huebbers C. U. , Siefer O. G. , Vent J. , Engbert I. , Eslick G. D. , Valter M. , Klussmann J. P. , Preuss S. F. . ( 2014;). Prevalence and risk factors for oral human papillomavirus infection in 129 women screened for cervical HPV infection. Oral Oncol 50: 27–31 [CrossRef] [PubMed].
    [Google Scholar]
  46. Micalessi M. I. , Boulet G. A. , Bogers J. . ( 2015;). A real-time PCR approach based on SPF10 primers and the INNO-LiPA HPV genotyping extra assay for the detection and typing of human papillomavirus. Methods Mol Biol 1249: 27–35 [CrossRef] [PubMed].
    [Google Scholar]
  47. Mostad S. B. , Kreiss J. K. , Ryncarz A. , Chohan B. , Mandaliya K. , Ndinya-Achola J. , Bwayo J. J. , Corey L. . ( 2000;). Cervical shedding of herpes simplex virus and cytomegalovirus throughout the menstrual cycle in women infected with human immunodeficiency virus type 1. Am J Obstet Gynecol 183: 948–955 [CrossRef] [PubMed].
    [Google Scholar]
  48. Nicholls P. K. , Moore P. F. , Anderson D. M. , Moore R. A. , Parry N. R. , Gough G. W. , Stanley M. A. . ( 2001;). Regression of canine oral papillomas is associated with infiltration of CD4+ and CD8+ lymphocytes. Virology 283: 31–39 [CrossRef] [PubMed].
    [Google Scholar]
  49. O'Brien W. A. . ( 1992;). Viral determinants of cellular tropism. Pathobiology 60: 225–233 [CrossRef] [PubMed].
    [Google Scholar]
  50. Ortiz A. P. , Romaguera J. , Pérez C. M. , Otero Y. , Soto-Salgado M. , Méndez K. , Valle Y. , Da Costa M. , Suarez E. , other authors . ( 2013;). Human papillomavirus infection in women in Puerto Rico: agreement between physician-collected and self-collected anogenital specimens. J Low Genit Tract Dis 17: 210–217 [CrossRef] [PubMed].
    [Google Scholar]
  51. Provenzano M. , Mocellin S. . ( 2007;). Complementary techniques: validation of gene expression data by quantitative real time PCR. Adv Exp Med Biol 593: 66–73 [CrossRef] [PubMed].
    [Google Scholar]
  52. Roberts J. N. , Buck C. B. , Thompson C. D. , Kines R. , Bernardo M. , Choyke P. L. , Lowy D. R. , Schiller J. T. . ( 2007;). Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nat Med 13: 857–861 [CrossRef] [PubMed].
    [Google Scholar]
  53. Rosenberger J. G. , Dodge B. , Van Der Pol B. , Reece M. , Herbenick D. , Fortenberry J. D. . ( 2011;). Reactions to self-sampling for ano-rectal sexually transmitted infections among men who have sex with men: a qualitative study. Arch Sex Behav 40: 281–288 [CrossRef] [PubMed].
    [Google Scholar]
  54. Ryan K. D. , Schwartz N. B. . ( 1977;). Grouped female mice: demonstration of pseudopregnancy. Biol Reprod 17: 578–583.[CrossRef]
    [Google Scholar]
  55. Sathish N. , Wang X. , Yuan Y. . ( 2014;). Human papillomavirus (HPV)-associated oral cancers and treatment strategies. J Dent Res 93: (Suppl), 29S–36S [CrossRef] [PubMed].
    [Google Scholar]
  56. Schmeink C. E. , Massuger L. F. , Lenselink C. H. , Quint W. G. , Melchers W. J. , Bekkers R. L. . ( 2010;). Effect of the menstrual cycle and hormonal contraceptives on human papillomavirus detection in young, unscreened women. Obstet Gynecol 116: 67–75 [CrossRef] [PubMed].
    [Google Scholar]
  57. Sehnal B. , Dusek L. , Cibula D. , Zima T. , Halaska M. , Driak D. , Slama J. . ( 2014;). The relationship between the cervical and anal HPV infection in women with cervical intraepithelial neoplasia. J Clin Virol 59: 18–23 [CrossRef] [PubMed].
    [Google Scholar]
  58. Stewart D. E. , Gagliardi A. , Johnston M. , Howlett R. , Barata P. , Lewis N. , Oliver T. , Mai V. , HPV Self-collection Guidelines Panel . ( 2007;). Self-collected samples for testing of oncogenic human papillomavirus: a systematic review. J Obstet Gynaecol Can 29: 817–828 [PubMed].
    [Google Scholar]
  59. Stier E. A. , Sebring M. C. , Mendez A. E. , Ba F. S. , Trimble D. D. , Chiao E. Y. . ( 2015;). Prevalence of anal human papillomavirus infection and anal HPV-related disorders in women: a systematic review. Am J Obstet Gynecol 213: 278–309 [CrossRef] [PubMed].
    [Google Scholar]
  60. Sun J. D. , Weatherly R. A. , Koopmann C.F., Jr , Carey T. E. . ( 2000;). Mucosal swabs detect HPV in laryngeal papillomatosis patients but not family members. Int J Pediatr Otorhinolaryngol 53: 95–103 [CrossRef] [PubMed].
    [Google Scholar]
  61. Sundberg J. P. , Stearns T. M. , Joh J. , Proctor M. , Ingle A. , Silva K. A. , Dadras S. S. , Jenson A. B. , Ghim S. J. . ( 2014;). Immune status, strain background, and anatomic site of inoculation affect mouse papillomavirus (MmuPV1) induction of exophytic papillomas or endophytic trichoblastomas. PLoS One 9: e113582 [PubMed].[CrossRef]
    [Google Scholar]
  62. Taghian A. , Huang P. . ( 1995;). The nude and SCID mice as a tumor model in experimental cancer biology. Cancer J 8: 52–58.
    [Google Scholar]
  63. Teepe A. G. , Allen L. B. , Wordinger R. J. , Harris E. F. . ( 1990;). Effect of the estrous cycle on susceptibility of female mice to intravaginal inoculation of herpes simplex virus type 2 (HSV-2). Antiviral Res 14: 227–235 [CrossRef] [PubMed].
    [Google Scholar]
  64. Ting J. , Rositch A. F. , Taylor S. M. , Rahangdale L. , Soeters H. M. , Sun X. , Smith J. S. . ( 2014;). Worldwide incidence of cervical lesions: a systematic review. Epidemiol Infect 143: 225–241 [PubMed].[CrossRef]
    [Google Scholar]
  65. Tota J. E. , Ramanakumar A. V. , Mahmud S. M. , Trevisan A. , Villa L. L. , Franco E. L. , Ludwig-McGill Cohort Study Group . ( 2013;). Cervical human papillomavirus detection is not affected by menstrual phase. Sex Transm Infect 89: 202–206 [CrossRef] [PubMed].
    [Google Scholar]
  66. Ure A. E. , Forslund O. . ( 2014;). Characterization of human papillomavirus type 154 and tissue tropism of gammapapillomaviruses. PLoS One 9: e89342 [CrossRef] [PubMed].
    [Google Scholar]
  67. Walker Q. D. , Nelson C. J. , Smith D. , Kuhn C. M. . ( 2002;). Vaginal lavage attenuates cocaine-stimulated activity and establishes place preference in rats. Pharmacol Biochem Behav 73: 743–752 [CrossRef] [PubMed].
    [Google Scholar]
  68. Waxman A. G. . ( 2008;). Cervical cancer screening in the early post vaccine era. Obstet Gynecol Clin North Am 35: 537–548.[CrossRef]
    [Google Scholar]
  69. Wells J. S. , Holstad M. M. , Thomas T. , Bruner D. W. . ( 2014;). An integrative review of guidelines for anal cancer screening in HIV-infected persons. AIDS Patient Care STDS 28: 350–357 [CrossRef] [PubMed].
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000295
Loading
/content/journal/jgv/10.1099/jgv.0.000295
Loading

Data & Media loading...

Supplements

Supplementary Data



PDF

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error