• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jvirolPermissionsJournals.ASM.orgJournalJV ArticleJournal InfoAuthorsReviewers
J Virol. Mar 1997; 71(3): 2463–2472.
PMCID: PMC191357

Human papillomavirus type 16 sequence variation in cervical cancers: a worldwide perspective.


We examined intratype human papillomavirus type 16 (HPV-16) sequence variation in tumor samples that were collected and analyzed in an international study of invasive cervical cancer. The collection included tumors from 22 countries in five continents. Using our recently developed E6 and L1 PCR-based hybridization systems to distinguish HPV-16 variant lineages, we analyzed material from tumors previously found to contain HPV-16 DNA. Of 408 specimens analyzed in the E6 hybridization assay, 376 (92.2%) belonged to previously reported HPV-16 variant lineages. The remaining 32 specimens (7.8%) harbored HPV-16 variants with novel hybridization patterns, novel nucleotide changes, or both. Nucleotide sequences (1,203 bp) were determined for the E6, the MY09/11 region of L1, and the long control region of each novel variant and representative specimens from each hybridization pattern observed. Based on E6 hybridization patterns, most of the variants from European and North American samples were phylogenetically classified as European prototype (E) while samples from Africa contained primarily African 1 (Af1) or African 2 (Af2) variants. The majority of Asian (As) variants were observed in Southeast Asia, and almost all Asian American (AA) variants were from Central and South America or Spain. A single North American 1 (NA1) variant was detected in a tumor from Argentina. Nucleotide changes previously shown to covary between the MY09/11 region of L1 and the E6 coding region were examined in a subset of 249 specimens. We observed 22 combined E6-L1 hybridization patterns, of which 11 (in 21 samples) were novel. No unanticipated nucleotide covariation was observed between the E class and the AA-Af1-Af2-NA1 classes, suggesting the absence or rarity of genomic recombination between HPV-16 lineages. This extensive description of HPV-16 variants forms a basis for further examining the relationship between intratype variation and basic functional differences in biological activities. HPV-16 variants may prove important for the determination of the risk of cervical neoplasia and for the design of HPV-16 vaccine strategies.

Full Text

The Full Text of this article is available as a PDF (635K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bavin PJ, Walker PG, Emery VC. Sequence microheterogeneity in the long control region of clinical isolates of human papillomavirus type 16. J Med Virol. 1993 Apr;39(4):267–272. [PubMed]
  • Bernard HU, Chan SY, Manos MM, Ong CK, Villa LL, Delius H, Peyton CL, Bauer HM, Wheeler CM. Identification and assessment of known and novel human papillomaviruses by polymerase chain reaction amplification, restriction fragment length polymorphisms, nucleotide sequence, and phylogenetic algorithms. J Infect Dis. 1994 Nov;170(5):1077–1085. [PubMed]
  • Bosch FX, Manos MM, Muñoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shah KV. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst. 1995 Jun 7;87(11):796–802. [PubMed]
  • Cheng G, Icenogle JP, Kirnbauer R, Hubbert NL, St Louis ME, Han C, Svare EI, Kjaer SK, Lowy DR, Schiller JT. Divergent human papillomavirus type 16 variants are serologically cross-reactive. J Infect Dis. 1995 Dec;172(6):1584–1587. [PubMed]
  • Stöppler MC, Ching K, Stöppler H, Clancy K, Schlegel R, Icenogle J. Natural variants of the human papillomavirus type 16 E6 protein differ in their abilities to alter keratinocyte differentiation and to induce p53 degradation. J Virol. 1996 Oct;70(10):6987–6993. [PMC free article] [PubMed]
  • Ellis JR, Keating PJ, Baird J, Hounsell EF, Renouf DV, Rowe M, Hopkins D, Duggan-Keen MF, Bartholomew JS, Young LS, et al. The association of an HPV16 oncogene variant with HLA-B7 has implications for vaccine design in cervical cancer. Nat Med. 1995 May;1(5):464–470. [PubMed]
  • Eluf-Neto J, Booth M, Muñoz N, Bosch FX, Meijer CJ, Walboomers JM. Human papillomavirus and invasive cervical cancer in Brazil. Br J Cancer. 1994 Jan;69(1):114–119. [PMC free article] [PubMed]
  • Eschle D, Dürst M, ter Meulen J, Luande J, Eberhardt HC, Pawlita M, Gissmann L. Geographical dependence of sequence variation in the E7 gene of human papillomavirus type 16. J Gen Virol. 1992 Jul;73(Pt 7):1829–1832. [PubMed]
  • Fujinaga Y, Okazawa K, Nishikawa A, Yamakawa Y, Fukushima M, Kato I, Fujinaga K. Sequence variation of human papillomavirus type 16 E7 in preinvasive and invasive cervical neoplasias. Virus Genes. 1994 Sep;9(1):85–92. [PubMed]
  • Hecht JL, Kadish AS, Jiang G, Burk RD. Genetic characterization of the human papillomavirus (HPV) 18 E2 gene in clinical specimens suggests the presence of a subtype with decreased oncogenic potential. Int J Cancer. 1995 Jan 27;60(3):369–376. [PubMed]
  • Ho L, Chan SY, Chow V, Chong T, Tay SK, Villa LL, Bernard HU. Sequence variants of human papillomavirus type 16 in clinical samples permit verification and extension of epidemiological studies and construction of a phylogenetic tree. J Clin Microbiol. 1991 Sep;29(9):1765–1772. [PMC free article] [PubMed]
  • Ho L, Tay SK, Chan SY, Bernard HU. Sequence variants of human papillomavirus type 16 from couples suggest sexual transmission with low infectivity and polyclonality in genital neoplasia. J Infect Dis. 1993 Oct;168(4):803–809. [PubMed]
  • Icenogle JP, Laga M, Miller D, Manoka AT, Tucker RA, Reeves WC. Genotypes and sequence variants of human papillomavirus DNAs from human immunodeficiency virus type 1-infected women with cervical intraepithelial neoplasia. J Infect Dis. 1992 Dec;166(6):1210–1216. [PubMed]
  • Icenogle JP, Sathya P, Miller DL, Tucker RA, Rawls WE. Nucleotide and amino acid sequence variation in the L1 and E7 open reading frames of human papillomavirus type 6 and type 16. Virology. 1991 Sep;184(1):101–107. [PubMed]
  • Kirnbauer R, Taub J, Greenstone H, Roden R, Dürst M, Gissmann L, Lowy DR, Schiller JT. Efficient self-assembly of human papillomavirus type 16 L1 and L1-L2 into virus-like particles. J Virol. 1993 Dec;67(12):6929–6936. [PMC free article] [PubMed]
  • Koutsky LA, Holmes KK, Critchlow CW, Stevens CE, Paavonen J, Beckmann AM, DeRouen TA, Galloway DA, Vernon D, Kiviat NB. A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med. 1992 Oct 29;327(18):1272–1278. [PubMed]
  • Londesborough P, Ho L, Terry G, Cuzick J, Wheeler C, Singer A. Human papillomavirus genotype as a predictor of persistence and development of high-grade lesions in women with minor cervical abnormalities. Int J Cancer. 1996 Oct 21;69(5):364–368. [PubMed]
  • Matsukura T, Kanda T, Furuno A, Yoshikawa H, Kawana T, Yoshiike K. Cloning of monomeric human papillomavirus type 16 DNA integrated within cell DNA from a cervical carcinoma. J Virol. 1986 Jun;58(3):979–982. [PMC free article] [PubMed]
  • Muñoz N, Bosch FX, de Sanjosé S, Tafur L, Izarzugaza I, Gili M, Viladiu P, Navarro C, Martos C, Ascunce N, et al. The causal link between human papillomavirus and invasive cervical cancer: a population-based case-control study in Colombia and Spain. Int J Cancer. 1992 Nov 11;52(5):743–749. [PubMed]
  • Pushko P, Sasagawa T, Cuzick J, Crawford L. Sequence variation in the capsid protein genes of human papillomavirus type 16. J Gen Virol. 1994 Apr;75(Pt 4):911–916. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • Schiffman MH, Bauer HM, Hoover RN, Glass AG, Cadell DM, Rush BB, Scott DR, Sherman ME, Kurman RJ, Wacholder S, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst. 1993 Jun 16;85(12):958–964. [PubMed]
  • Seedorf K, Krämmer G, Dürst M, Suhai S, Röwekamp WG. Human papillomavirus type 16 DNA sequence. Virology. 1985 Aug;145(1):181–185. [PubMed]
  • Smits HL, Traanberg KF, Krul MR, Prussia PR, Kuiken CL, Jebbink MF, Kleyne JA, van den Berg RH, Capone B, de Bruyn A, et al. Identification of a unique group of human papillomavirus type 16 sequence variants among clinical isolates from Barbados. J Gen Virol. 1994 Sep;75(Pt 9):2457–2462. [PubMed]
  • Stewart AC, Eriksson AM, Manos MM, Muñoz N, Bosch FX, Peto J, Wheeler CM. Intratype variation in 12 human papillomavirus types: a worldwide perspective. J Virol. 1996 May;70(5):3127–3136. [PMC free article] [PubMed]
  • Wheeler CM, Yamada T, Hildesheim A, Jenison SA. Human papillomavirus type 16 sequence variants: identification by E6 and L1 lineage-specific hybridization. J Clin Microbiol. 1997 Jan;35(1):11–19. [PMC free article] [PubMed]
  • Xi LF, Demers GW, Koutsky LA, Kiviat NB, Kuypers J, Watts DH, Holmes KK, Galloway DA. Analysis of human papillomavirus type 16 variants indicates establishment of persistent infection. J Infect Dis. 1995 Sep;172(3):747–755. [PubMed]
  • Yamada T, Wheeler CM, Halpern AL, Stewart AC, Hildesheim A, Jenison SA. Human papillomavirus type 16 variant lineages in United States populations characterized by nucleotide sequence analysis of the E6, L2, and L1 coding segments. J Virol. 1995 Dec;69(12):7743–7753. [PMC free article] [PubMed]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...