1887

Abstract

Integrated human papillomavirus type 16 (HPV-16) viral loads are currently estimated by quantification with real-time PCR of HPV-16 E6 (RT-E6 and HPV-16 PG) and E2 (RT-E2-1) DNA. We assessed the influence of HPV-16 E2 polymorphism on quantification of integrated HPV-16 DNA in anogenital specimens. HPV-16 E2 was sequenced from 135 isolates (123 from European and 12 from non-European lineages). An assay targeting conserved HPV-16 E2 sequences (RT-E2-2) was optimized and applied with RT-E6 and RT-E2-1 on 139 HPV-16-positive cervicovaginal lavages collected from 74 women [58 human immunodeficiency virus (HIV)-seropositive and 16 HIV-seronegative]. Ratios of HPV-16 copies measured with RT-E2-2 and RT-E2-1 obtained with African 2 (median=3.23, range=1.92–3.49) or Asian–American (median=3.78, range=1.47–37) isolates were greater than those obtained with European isolates (median=1.02, range=0.64–1.80; <0.02 for each comparison). The distribution of HPV-16 E2 copies measured in 139 samples with RT-E2-2 (median=6150) and RT-E2-1 (median=8960) were different (<0.0001). The risk of high-grade cervical intraepithelial neoplasia (CIN-2,3) compared with women without CIN was increased with higher HPV-16 total [odds ratio (OR)=2.17, 95 % confidence interval (CI)=1.11–4.23], episomal (OR=2.14, 95 % CI=1.09–4.19), but not for HPV-16 integrated viral load (OR=1.71, 95 % CI=0.90–3.26), after controlling for age, race, CD4 count, HIV and HPV-16 polymorphism. The proportion of samples with an E6/E2 ratio >2 in women without squamous intraepithelial lesion (7 of 35) was similar to that of women with CIN-2,3 (5 of 11, =0.24) or CIN-1 (5 of 14, =0.50). HPV-16 E2 polymorphism was a significant factor that influenced measures of HPV-16 integrated viral load.

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2008-07-01
2019-11-22
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References

  1. Arias-Pulido, H., Peyton, C. L., Joste, N. E., Vargas, H. & Wheeler, C. M. ( 2006; ). Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer. J Clin Microbiol 44, 1755–1762.[CrossRef]
    [Google Scholar]
  2. Casas, L., Galvan, S. C., Ordonez, R. M., Lopez, N., Guido, M. & Berumen, J. ( 1999; ). Asian–American variants of human papillomavirus type 16 have extensive mutations in the E2 gene and are highly amplified in cervical carcinomas. Int J Cancer 83, 449–455.[CrossRef]
    [Google Scholar]
  3. Cheung, J. L., Lo, K. W., Cheung, T. H., Tang, J. W. & Chan, P. K. ( 2006; ). Viral load, E2 gene disruption status, and lineage of human papillomavirus type 16 infection in cervical neoplasia. J Infect Dis 194, 1706–1712.[CrossRef]
    [Google Scholar]
  4. Clifford, G. M., Smith, J. S., Aguado, T. & Franceschi, S. ( 2003; ). Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis. Br J Cancer 89, 101–105.[CrossRef]
    [Google Scholar]
  5. Coutlée, F., Hankins, C. & Lapointe, N., The Canadian Women's HIV Study Group. ( 1997; ). Comparison between vaginal tampon and cervicovaginal lavage specimens collection for detection of human papillomavirus DNA by the polymerase chain reaction. J Med Virol 51, 42–47.[CrossRef]
    [Google Scholar]
  6. Dalstein, V., Riethmuller, D., Pretet, J. L., Le Bail, C., Sautiere, J. L., Carbillet, J. P., Kantelip, B., Schaal, J. P. & Mougin, C. ( 2003; ). Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study. Int J Cancer 106, 396–403.[CrossRef]
    [Google Scholar]
  7. De Marco, L., Gillio-Tos, A., Bonello, L., Ghisetti, V., Ronco, G. & Merletti, F. ( 2007; ). Detection of human papillomavirus type 16 integration in pre-neoplastic cervical lesions and confirmation by DIPS-PCR and sequencing. J Clin Virol 38, 7–13.[CrossRef]
    [Google Scholar]
  8. Eriksson, A., Herron, J. R., Yamada, T. & Wheeler, C. M. ( 1999; ). Human papillomavirus type 16 variant lineages characterized by nucleotide sequence analysis of the E5 coding segment and the E2 hinge region. J Gen Virol 80, 595–600.
    [Google Scholar]
  9. Ferenczy, A. & Franco, E. L. ( 2002; ). Persistent human papillomavirus infection and cervical neoplasia. Lancet Oncol 3, 11–16.[CrossRef]
    [Google Scholar]
  10. Ferenczy, A., Coutlée, F., Franco, E. L. & Hankins, C. ( 2003; ). HIV and HPV co-infection and lower genital tract neoplasia: review of recent developments. CMAJ 169, 431–434.
    [Google Scholar]
  11. Flores, R., Papenfuss, M., Klimecki, W. T. & Giuliano, A. R. ( 2006; ). Cross-sectional analysis of oncogenic HPV viral load and cervical intraepithelial neoplasia. Int J Cancer 118, 1187–1193.[CrossRef]
    [Google Scholar]
  12. Flores-Munguia, R., Siegel, E., Klimecki, W. T. & Giuliano, A. R. ( 2004; ). Performance assessment of eight-throughput PCR assays for viral load quantitation of oncogenic HPV types. J Mol Diagn 6, 115–124.[CrossRef]
    [Google Scholar]
  13. Fontaine, J., Hankins, C., Mayrand, M. H., Lefevre, J., Money, D., Gagnon, S., Rachlis, A., Pourreaux, K. & Coutlee, F. ( 2005a; ). High levels of episomal and integrated HPV-16 DNA are associated with high-grade cervical lesions in women at risk or infected with HIV. AIDS 19, 785–794.[CrossRef]
    [Google Scholar]
  14. Fontaine, J., Gravitt, P., Duh, L. M., Lefevre, J., Pourreaux, K., Hankins, C. & Coutlee, F. ( 2005b; ). High level of correlation of human papillomavirus-16 DNA viral load estimates generated by three real-time PCR assays applied on genital specimens. Cancer Epidemiol Biomarkers Prev 14, 2200–2207.[CrossRef]
    [Google Scholar]
  15. Fujii, T., Masumoto, N., Saito, M., Hirao, N., Niimi, S., Mukai, M., Ono, A., Hayashi, S., Kubushiro, K. & other authors ( 2005; ). Comparison between in situ hybridization and real-time PCR technique as a means of detecting the integrated form of human papillomavirus 16 in cervical neoplasia. Diagn Mol Pathol 14, 103–108.[CrossRef]
    [Google Scholar]
  16. Giannoudis, A., van Duin, M., Snijders, P. J. F. & Herrington, C. S. ( 2001; ). Variation in the E2-binding domain of HPV 16 is associated with high-grade squamous intraepithelial lesions of the cervix. Br J Cancer 84, 1058–1063.[CrossRef]
    [Google Scholar]
  17. Graham, D. A. & Herrington, C. S. ( 2000; ). HPV-16 E2 gene disruption and sequence variation in CIN 3 lesions and invasive squamous cell carcinomas of the cervix: relation to numerical chromosome abnormalities. Mol Pathol 53, 201–206.[CrossRef]
    [Google Scholar]
  18. Gravitt, P. E., Peyton, C., Wheeler, C., Apple, R., Higuchi, R. & Shah, K. V. ( 2003; ). Reproducibility of HPV 16 and HPV 18 viral load quantitation using TaqMan real-time PCR assays. J Virol Methods 112, 23–33.[CrossRef]
    [Google Scholar]
  19. Guo, M., Sneige, N., Silva, E. G., Jan, Y. J., Cogdell, D. E., Lin, E., Luthra, R. & Zhang, W. ( 2007; ). Distribution and viral load of eight oncogenic types of human papillomavirus (HPV) and HPV 16 integration status in cervical intraepithelial neoplasia and carcinoma. Mod Pathol 20, 256–266.[CrossRef]
    [Google Scholar]
  20. Hankins, C., Coutlee, F., Lapointe, N., Simard, P., Tran, T., Samson, J. & Hum, L., The Canadian Women's HIV Study Group. ( 1999; ). Prevalence of risk factors associated with human papillomavirus infection in women living with HIV. CMAJ 160, 185–191.
    [Google Scholar]
  21. Hopman, A. H. N., Smedts, F., Dignef, W., Ummulen, M., Sonke, G., Mravunac, M., Vooijs, G. P., Speel, E. J. M. & Ramaekers, F. C. S. ( 2004; ). Transition to high-grade cervical intraepithelial neoplasia to micro-invasive carcinoma is characterized by integration of HPV16/18 and numerical chromosome abnormalities. J Pathol 202, 23–33.[CrossRef]
    [Google Scholar]
  22. Josefsson, A. M., Magnusson, P. K. E., Ylitalo, N., Sorensen, P., Qwarforth-Tubbin, P., Anderson, P. K., Melbye, M., Adami, H. O. & Yllensten, U. B. ( 2000; ). Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case–control study. Lancet 355, 2189–2193.[CrossRef]
    [Google Scholar]
  23. Kalantari, M., Karlsen, F., Kristensen, G., Holm, R., Hagmar, B. & Johansson, B. ( 1998; ). Disruption of the E1 and E2 reading frames of HPV 16 in cervical carcinoma is associated with poor prognosis. Int J Gynecol Pathol 17, 146–153.[CrossRef]
    [Google Scholar]
  24. Khouadri, S., Villa, L. L., Gagnon, S., Koushik, A., Richardson, H., Ferenczy, A., Matlashewski, G., Roger, M., Franco, E. L. F. & Coutlée, F. ( 2007; ). Viral load of episomal and integrated forms of human papillomavirus type 33 in high-grade squamous intraepithelial lesions of the uterine cervix. Int J Cancer 121, 2674–2681.[CrossRef]
    [Google Scholar]
  25. Koushik, A., Ghosh, A., Duarte-Franco, E., Forest, P., Voyer, H., Matlashewski, G., Coutlee, F. & Franco, E. L. ( 2005; ). The p53 codon 72 polymorphism and risk of high-grade cervical intraepithelial neoplasia. Cancer Detect Prev 29, 307–316.[CrossRef]
    [Google Scholar]
  26. Kulmala, S.-M. A., Syrjanen, S. M., Gyllensten, U. B., Shabalova, I. P., Petrovichev, N., Tosi, P. T., Syrjanen, K. J. & Johansson, B. C. ( 2006; ). Early integration of high copy HPV-16 detectable in women with normal and low grade cervical cytology and histology. J Clin Pathol 59, 513–517.[CrossRef]
    [Google Scholar]
  27. Lefevre, J., Hankins, C., Pourreaux, K., Voyer, H. & Coutlée, F., The Canadian Women's HIV Study Group. ( 2003; ). Real-time PCR assays using internal controls for quantitation of HPV-16 and β-globin DNA in cervicovaginal lavages. J Virol Methods 144, 135–144.
    [Google Scholar]
  28. Lefevre, J., Hankins, C., Pourreaux, K. & Coutlée, F., The Canadian Women's HIV Study Group. ( 2004; ). Prevalence of selective inhibition of HPV-16 DNA amplification in cervicovaginal lavages. J Med Virol 72, 132–137.[CrossRef]
    [Google Scholar]
  29. Meissner, J. ( 1997; ). Sequencing errors in reference HPV clones. In Human Papillomavirus 1997: a Compilation and Analysis of Nucleic Acid and Amino Acid Sequences, pp. 110–123. Edited by G. Myers, K. Munger, F. Sverdrup, A. A. McBride, H. U. Bernard & J. Meissner. Los Alamos National Laboratory, NM.
  30. Moberg, M., Gustavsson, I. & Gyllensten, U. ( 2003; ). Real-time PCR-based system for simultaneous quantification of human papillomavirus types associated with high risk of cervical cancer. J Clin Microbiol 41, 3221–3228.[CrossRef]
    [Google Scholar]
  31. Moberg, M., Gustavsson, I. & Gyllensten, U. ( 2004; ). Type-specific associations of human papillomavirus load with risk of developing cervical carcinoma in situ. Int J Cancer 112, 854–859.[CrossRef]
    [Google Scholar]
  32. Moberg, M., Gustavsson, I., Wilander, E. & Gyllensten, U. ( 2005; ). High viral loads of human papillomavirus predict risk of invasive cervical carcinoma. Br J Cancer 92, 891–894.[CrossRef]
    [Google Scholar]
  33. Myers, G. B., Bernard, H.-U., Delius, H., Baker, C. C., Icenogle, J., Halpern, A. L. & Wheeler, C. ( 1995; ). Human Papillomavirus. A Compilation of Analysis of Nucleic Acid and Amino Acid Sequences. Publication LA-UR 95–3675 ed. Los Alamos, NM.
  34. Nagao, S., Yoshinouchi, M., Miyagi, Y., Hongo, A., Kodama, J., Itoh, S. & Kudo, T. ( 2002; ). Rapid and sensitive detection of physical status of human papillomavirus type 16 DNA by quantitative real-time PCR. J Clin Microbiol 40, 863–867.[CrossRef]
    [Google Scholar]
  35. Peitsaro, P., Johansson, B. & Syrjanen, S. ( 2002; ). Integrated human papillomavirus type 16 is frequently found in cervical cancer precursors as demonstrated by a novel quantitative real-time PCR technique. J Clin Microbiol 40, 886–891.[CrossRef]
    [Google Scholar]
  36. Rajeevan, M. S., Swan, D. C., Nisenbaum, R., Lee, D. R., Vernon, S. D., Ruffin, M. T., Horowitz, I. R., Flowers, L. C., Kmak, D. & other authors ( 2005; ). Epidemiologic and viral factors associated with cervical neoplasia in HPV-16-positive women. Int J Cancer 115, 114–120.[CrossRef]
    [Google Scholar]
  37. Sathish, N., Abraham, P., Peedicayil, A., Sridharan, G., Shaji, R. V. & Chandy, G. ( 2004; ). E2 sequence variations of HPV 16 among patients with cervical neoplasia seen in the Indian subcontinent. Gynecol Oncol 95, 363–369.[CrossRef]
    [Google Scholar]
  38. Schlecht, N. F., Trevisan, A., Duarte-Franco, E., Rohan, T. E., Ferenczy, A., Villa, L. L. & Franco, E. L. ( 2003; ). Viral load as a predictor of the risk of cervical intraepithelial neoplasia. Int J Cancer 103, 519–524.[CrossRef]
    [Google Scholar]
  39. Swan, D. C., Rajeevan, M., Tortolero-Luna, G., Follen, M., Tucker, R. A. & Unger, E. R. ( 2005; ). Human papillomavirus type 16 E2 and E6/E7 variants. Gynecol Oncol 96, 695–700.[CrossRef]
    [Google Scholar]
  40. van Duin, M., Snidjers, P. J. F., Schrijnemakers, H. F. J., Voorhorst, F. J., Rozendaal, L., Nobbenhuis, M. A. E., van den Brule, A. J. C., Verheijen, R. H. M., Helmerhorst, T. J. & Meijer, C. J. L. M. ( 2002; ). Human papillomavirus 16 load in normal and abnormal cervical scrapes: an indicator of CIN II/III and viral clearance. Int J Cancer 98, 590–595.[CrossRef]
    [Google Scholar]
  41. Veress, G., Szarka, K., Dong, X. P., 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, 1035–1043.
    [Google Scholar]
  42. Wang, S. S. & Hildesheim, A. ( 2003; ). Chapter 5: Viral and host factors in human papillomavirus persistence and progression. J Natl Cancer Inst Monogr 2003, 35–40.[CrossRef]
    [Google Scholar]
  43. Watts, K. J., Thompson, C. H., Cossart, Y. E. & Rose, B. R. ( 2002; ). Sequence variation and physical state of human papillomavirus type 16 cervical cancer isolates from Australia and New Caledonia. Int J Cancer 97, 868–874.[CrossRef]
    [Google Scholar]
  44. Whiley, D. M. & Sloots, T. P. ( 2005; ). Sequence variation in primer targets affects the accuracy of viral quantitative PCR. J Clin Virol 34, 104–107.[CrossRef]
    [Google Scholar]
  45. Ylitalo, N., Sorensen, P., Josefsson, A. M., Magnusson, P. K. E., Anderson, P. K., Ponten, J., Adami, H. O., Gyllensten, U B. & Melbye, M. ( 2000; ). Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case–control study. Lancet 355, 2194–2198.[CrossRef]
    [Google Scholar]
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