Medical Microbiology and Immunology

, Volume 202, Issue 5, pp 353–363

Genomic differences in the background of different severity in juvenile-onset respiratory papillomatoses associated with human papillomavirus type 11

  • Tamás Gáll
  • Andrea Kis
  • Tímea Zsófia Tatár
  • Gábor Kardos
  • Lajos Gergely
  • Krisztina Szarka
Original Investigation

Abstract

This study aimed to compare complete genome sequences of human papillomavirus (HPV) type 11 from two solitary papillomas (considered minimally aggressive), two moderately (six and nine episodes) and two highly aggressive (30 and 33 episodes) juvenile-onset respiratory papillomatoses. Genomic regions were sequenced using the Sanger method; sequences were compared to available GenBank genomes. Activity of the long control region (LCR) was assessed in HEp-2 cell line using luciferase assays and compared to that of the reference (GenBank Accession Number M14119). Site-directed mutagenesis was performed to confirm the association of polymorphisms with differences in LCR activity. Eleven alterations resulted in amino acid changes in different open reading frames. A72E in E1 and Q86K in E2 proteins were exclusively present in a moderately aggressive disease, L1 alterations A476V and S486F were unique to a severe papillomatosis. HPV11s in both solitary papillomas had identical LCRs containing a T7546C polymorphism, which strongly attenuated LCR activity, as confirmed by site-directed mutagenesis. This strong attenuator polymorphism was also present in the other four genomes showing significantly higher activities, but in these other alterations with demonstrable but statistically not significant attenuating (A7413C, 7509 T deletion) or enhancing (C7479T, T7904A) effect on transactivating potential (as demonstrated by site-directed mutagenesis) were also detected. LCR activities corresponded well to severity, excepting the highly aggressive papillomatosis with the L1 alterations. Presence of intratypic variants cannot explain differences in severity of respiratory papillomatoses associated with HPV11; virulence seems to be determined by the interaction of multiple genetic differences.

Keywords

HPV11 Complete genome comparison LCR activity Clinical course 

References

  1. 1.
    Derkay CS (2001) Recurrent respiratory papillomatosis. Laryngoscope 111:57–69PubMedCrossRefGoogle Scholar
  2. 2.
    Kashima H, Mounts P, Leventhal B, Hruban RH (1993) Sites of predilection in recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 102:580–583PubMedGoogle Scholar
  3. 3.
    Dickens P, Srivastava G, Loke SL, Larkin S (1991) Human papillomavirus 6, 11, and 16 in laryngeal papillomas. J Pathol 165:243–246PubMedCrossRefGoogle Scholar
  4. 4.
    Steinberg BM, DiLorenzo TP (1996) A possible role for human papillomaviruses in head and neck cancer. Cancer Metastasis Rev 15:91–112PubMedCrossRefGoogle Scholar
  5. 5.
    Lee LA, Cheng AJ, Fang TJ, Huang CG, Liao CT, Chang JT, Li HY (2008) High incidence of malignant transformation of laryngeal papilloma in Taiwan. Laryngoscope 118:50–55PubMedCrossRefGoogle Scholar
  6. 6.
    Rabah R, Lancaster WD, Thomas R, Gregoire L (2001) Human papillomavirus-11-associated recurrent respiratory papillomatosis is more aggressive than human papillomavirus-6-associated disease. Pediatr Dev Pathol 4:68–72PubMedCrossRefGoogle Scholar
  7. 7.
    Wiatrak BJ, Wiatrak DW, Broker TR, Lewis L (2004) Recurrent respiratory papillomatosis: a longitudinal study comparing severity associated with human papilloma viral types 6 and 11 and other risk factors in a large pediatric population. Laryngoscope 114:S1–S23CrossRefGoogle Scholar
  8. 8.
    James EA, DeVoti JA, Rosenthal DW, Hatam LJ, Steinberg BM, Abramson AL, Kwok WW, Bonagura VR (2011) Papillomavirus-specific CD4(+) T cells exhibit reduced STAT-5 signaling and altered cytokine profiles in patients with recurrent respiratory papillomatosis. J Immunol 186:6633–6670PubMedCrossRefGoogle Scholar
  9. 9.
    Lucs AV, Wu R, Mullooly V, Abramson AL, Steinberg BM (2012) Constitutive overexpression of the oncogene Rac1 in the airway of recurrent respiratory papillomatosis patients is a targetable host-susceptibility factor. Mol Med 18:244–249PubMedCrossRefGoogle Scholar
  10. 10.
    Yamada T, Manos MM, Peto J, Greer CE, Munoz N, Bosch FX, Wheeler CM (1997) Human papillomavirus type 16 sequence variation in cervical cancers: a worldwide perspective. J Virol 71:2463–2472PubMedGoogle Scholar
  11. 11.
    Xi LF, Koutsky LA, Galloway DA, Kuypers J, Hughes JP, Wheeler CM, Holmes KK, Kiviat NB (1997) Genomic variation of human papillomavirus type 16 and risk for high grade cervical intraepithelial neoplasia. J Natl Cancer Inst 89:796–802PubMedCrossRefGoogle Scholar
  12. 12.
    Villa LL, Sichero L, Rahal P, Caballero O, Ferenczy A, Rohan T, Franco EL (2000) Molecular variants of human papillomavirus types 16 and 18 preferentially associated with cervical neoplasia. J Gen Virol 81:2959–2968PubMedGoogle Scholar
  13. 13.
    Berumen J, Ordonez RM, Lazcano E, Salmeron J, Galvan SC, Estrada RA, Yunes E, Garcia-Carranca A, Gonzalez-Lira G, Madrigal-de la Campa A (2001) Asian-American variants of human papillomavirus 16 and risk for cervical cancer: a case-control study. J Natl Cancer Inst 93:1325–1330PubMedCrossRefGoogle Scholar
  14. 14.
    Hildesheim A, Schiffman MH, Bromley C, Wacholder S, Herrero R, Rodriguez A, Bratti MC, Sherman ME, Scarpidis U, Lin QQ, Terai M, Bromley RL, Buetow K, Apple RJ, Burk RD (2001) Human papillomavirus type 16 variants and risk of cervical cancer. J Natl Cancer Inst 93:315–318PubMedCrossRefGoogle Scholar
  15. 15.
    Xi LF, Carter JJ, Galloway DA, Hughes JP, Lee SK, Adam DE, Kiviat NB, Koutsky LA (2002) Acquisition and natural history of human papillomavirus type 16 variant infection among a cohort of female university students. Cancer Epidemiol Biomarkers Prev 11:343–351PubMedGoogle Scholar
  16. 16.
    Pista A, Oliveira A, Barateiro A, Costa H, Verdasca N, Paixao MT (2007) Molecular variants of human papillomavirus type 16 and 18 and risk for cervical neoplasia in Portugal. J Med Virol 79:1889–1897PubMedCrossRefGoogle Scholar
  17. 17.
    Tornesello ML, Duraturo ML, Losito S, Botti G, Pilotti S, Stefanon B, De Palo G, Gallo A, Buonaguro L, Buonaguro FM (2008) Human papillomavirus genotypes and HPV16 variants in penile carcinoma. Int J Cancer 122:132–137PubMedCrossRefGoogle Scholar
  18. 18.
    May M, Dong XP, Beyer-Finkler E, Stubenrauch F, Fuchs PG, Pfister H (1994) The E6/E7 promoter of extrachromosomal HPV16 DNA in cervical cancers escapes from cellular repression by mutation of target sequences for YY1. EMBO J 13:1460–1466PubMedGoogle Scholar
  19. 19.
    Veress G, Szarka K, Dong XP, Gergely L, Pfister H (1999) Functional significance of sequence variation in the E2 gene and the long control region of human papillomavirus type 16. J Gen Virol 80:1035–1043PubMedGoogle Scholar
  20. 20.
    Schmidt M, Kedzia W, Goździcka-Józefiak A (2001) Intratype HPV16 sequence variation within LCR of isolates from asymptomatic carriers and cervical cancers. J Clin Virol 23:65–77PubMedCrossRefGoogle Scholar
  21. 21.
    Veress G, Murvai M, Szarka K, Juhász A, Kónya J, Gergely L (2001) Transcriptional activity of human papillomavirus type 16 variants having deletions in the long control region. Eur J Cancer 37:1946–1952PubMedCrossRefGoogle Scholar
  22. 22.
    Xin CY, Matsumoto K, Yoshikawa H, Yasugi T, Onda T, Nakagawa S, Yamada M, Nozawa S, Sekiya S, Hirai Y, Shiromizu K, Tomoyuki Fujii T, Taketani Y (2001) Analysis of E6 variants of human papillomavirus type 33, 52 and 58 in Japanese women with cervical intraepithelial neoplasia/cervical cancer in relation to their oncogenic potential. Cancer Lett 170:19–24PubMedCrossRefGoogle Scholar
  23. 23.
    Burk RD, Terai M, Gravitt PE, Brinton LA, Kurman RJ, Barnes WA, Greenberg MD, Hadjimichael OC, Fu L, McGowan L, Mortel R, Schwartz PE, Hildesheim A (2003) Distribution of human papillomavirus types 16 and 18 variants in squamous cell carcinomas and adenocarcinomas of the cervix. Cancer Res 63:7215–7220PubMedGoogle Scholar
  24. 24.
    Lizano M, De la Cruz-Hernandez E, Carrillo-Garcia A, Garcia-Carranca A, de Leon-Rosales SP, Duenas-Gonzalez A, Hernandez–Hernandez DM, Mohar A (2006) Distribution of HPV16 and 18 intratypic variants in normal cytology, intraepithelial lesions, and cervical cancer in a Mexican population. Gynecol Oncol 102:230–235PubMedCrossRefGoogle Scholar
  25. 25.
    Heinzel PA, Chan SY, Ho L, O’Connor M, Balaram P, Campo MS, Fujinaga K, Kiviat N, Kuypers J, Pfister H, Steinberg BM, Tay SK, Villa LL, Bernard HU (1995) Variation of human papillomavirus type 6 (HPV-6) and HPV-11 genomes sampled throughout the world. J Clin Microbiol 33:1746–1754PubMedGoogle Scholar
  26. 26.
    Burk RD, Chen Z, Harari A, Smith BC, Kocjan BJ, Maver PJ, Poljak M (2011) Classification and nomenclature system for human Alphapapillomavirus variants: general features, nucleotide landmarks and assignment of HPV6 and HPV11 isolates to variant lineages. Acta Dermatovenerol Alp Panonica Adriat 20:113–123PubMedGoogle Scholar
  27. 27.
    Maver PJ, Kocjan BJ, Seme K, Potočnik M, Gale N, Poljak M (2011) Prevaccination genomic diversity of human papillomavirus genotype 11: a study on 63 clinical isolates and 10 full-length genome sequences. J Med Virol 83:461–470PubMedCrossRefGoogle Scholar
  28. 28.
    Derkay CS, Malis DJ, Zalzal G, Wiatrak BJ, Kashima HK, Coltrera MD (1998) A staging system for assessing severity of disease and response to therapy in recurrent respiratory papillomatosis. Laryngoscope 108:935–937PubMedCrossRefGoogle Scholar
  29. 29.
    Gáll T, Kis A, Fehér E, Gergely L, Szarka K (2011) Virological failure of intralesional cidofovir therapy in recurrent respiratory papillomatosis is not associated with genetic or epigenetic changes of HPV11: complete genome comparison of sequential isolates. Antiviral Res 92:356–358PubMedCrossRefGoogle Scholar
  30. 30.
    Gissmann L, Diehl V, Schultz-Coulon HJ, zur Hausen H (1982) Molecular cloning and characterization of human papilloma virus DNA derived from a laryngeal papilloma. J Virol 44:393–400PubMedGoogle Scholar
  31. 31.
    Dartmann K, Schwarz E, Gissmann L, zur Hausen H (1986) The nucleotide sequence and genome organization of human papillomavirus type 11. Virology 151:124–130PubMedCrossRefGoogle Scholar
  32. 32.
    Wu X, Zhang C, Feng S, Liu C, Li Y, Yang Y, Gao J, Li H, Meng S, Li L, Zhang Y, Hu X, Wu X, Lin L, Li X, Wang Y (2009) Detection of HPV types and neutralizing antibodies in Gansu province, China. J Med Virol 81:693–702PubMedCrossRefGoogle Scholar
  33. 33.
    Chansaenroj J, Theamboonlers A, Junyangdikul P, Supiyaphan P, Poovorawan Y (2012) Whole genome analysis of human papillomavirus genotype 11 from cervix, larynx and lung. Asian Pac J Cancer Prev 13:2619–2623PubMedCrossRefGoogle Scholar
  34. 34.
    Yuan H, Myers S, Wang J, Zhou D, Woo JA, Kallakury B, Ju A, Bazylewicz M, Carter YM, Albanese C, Grant N, Shad A, Dritschilo A, Liu X, Schlegel R (2012) Use of reprogrammed cells to identify therapy for respiratory papillomatosis. N Engl J Med 367:1220–1227PubMedCrossRefGoogle Scholar
  35. 35.
    Chung CT, Niemela SL, Miller RH (1989) One-step preparation of competent Escherichia coli: transformation and storage of bacterial cells in the same solution. Proc Natl Acad Sci USA 86:2172–2175PubMedCrossRefGoogle Scholar
  36. 36.
    Tornesello ML, Losito S, Benincasa G, Fulciniti F, Botti G, Greggi S, Buonaguro L, Buonaguro FM (2011) Human papillomavirus (HPV) genotypes and HPV16 variants and risk of adenocarcinoma and squamous cell carcinoma of the cervix. Gynecol Oncol 121:32–42PubMedCrossRefGoogle Scholar
  37. 37.
    Johnston D, Hall H, DiLorenzo TP, Steinberg BM (1999) Elevation of the epidermal growth factor receptor and dependent signalling in human papillomavirus-infected laryngeal papillomas. Cancer Res 59:968–974PubMedGoogle Scholar
  38. 38.
    DiMaio D, Mattoon D (2001) Mechanisms of cell transformation by papillomavirus E5 proteins. Oncogene 20:7866–7873PubMedCrossRefGoogle Scholar
  39. 39.
    Zehbe I, Wilander E, Delius H, Tommasino M (1998) Human papillomavirus 16 E6 variants are more prevalent in invasive cervical carcinoma than the prototype. Cancer Res 58:829–833PubMedGoogle Scholar
  40. 40.
    Zehbe I, Richard C, DeCarlo CA, Shai A, Lambert PF, Lichtig H, Tommasino M, Sherman L (2009) Human papillomavirus 16 E6 variants differ in their dysregulation of human keratinocyte differentiation and apoptosis. Virology 383:69–77PubMedCrossRefGoogle Scholar
  41. 41.
    Tornesello ML, Buonaguro FM, Buonaguro L, Salatiello I, Beth-Giraldo E, Giraldo G (2000) Identification and functional analysis of sequence rearrangements in the long control region of human papillomavirus type 16 Af-1 variants isolated from Ugandan penile carcinomas. J Gen Virol 81:2969–2982PubMedGoogle Scholar
  42. 42.
    Chiang CM, Ustav M, Stenlund A, Ho TF, Broker TR, Chow LT (1992) Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins. Proc Natl Acad Sci USA 89:5799–5803PubMedCrossRefGoogle Scholar
  43. 43.
    Bishop B, Dasgupta J, Chen XS (2007) Structure-based engineering of papillomavirus major capsid L1: controlling particle assembly. Virol J 4:3PubMedCrossRefGoogle Scholar
  44. 44.
    Yang R, Wheeler CM, Chen X, Uematsu S, Takeda K, Akira S, Pastrana DV, Viscidi RP, Roden RB (2005) Papillomavirus capsid mutation to escape dendritic cell-dependent innate immunity in cervical cancer. J Virol 79:6741–6750PubMedCrossRefGoogle Scholar
  45. 45.
    Lee K, Magalhaes I, Clavel C, Briolat J, Birembaut P, Tommasino M, Zehbe I (2008) Human papillomavirus 16 E6, L1, L2 and E2 gene variants in cervical lesion progression. Virus Res 131:106–110PubMedCrossRefGoogle Scholar
  46. 46.
    Hoppe-Seyler F, Butz K (1994) Cellular control of human papillomavirus oncogene transcription. Mol Carcinog 10:134–141PubMedCrossRefGoogle Scholar
  47. 47.
    O’Connor M, Chan SY, Bernard HU (1995) Transcription factor binding sites in the long control region of genital HPVs. In: Myer G, Bernard HU, Delius H, Baker C, Icenogle J, Halpern A, Wheeler C (eds) Human papillomaviruses 1995 compendium, vol III-A. Los Alamos National Laboratory, Los Alamos, pp 21–44Google Scholar
  48. 48.
    Kammer C, Warthorst U, Torrez-Martinez N, Wheeler CM, Pfister H (2000) Sequence analysis of the long control region of human papillomavirus type 16 variants and functional consequences for P97 promoter activity. J Gen Virol 81:1975–1981PubMedGoogle Scholar
  49. 49.
    Lace MJ, Isacson C, Anson JR, Lörincz AT, Wilczynski SP, Haugen TH, Turek LP (2009) Upstream regulatory region alterations found in human papillomavirus type 16 (HPV-16) isolates from cervical carcinomas increase transcription, ori function, and HPV immortalization capacity in culture. J Virol 83:7457–7466PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Tamás Gáll
    • 1
  • Andrea Kis
    • 1
  • Tímea Zsófia Tatár
    • 1
  • Gábor Kardos
    • 1
  • Lajos Gergely
    • 1
  • Krisztina Szarka
    • 1
  1. 1.Department of Medical Microbiology, Medical and Health Science CentreUniversity of DebrecenDebrecenHungary

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