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Journal of Virology, August 2009, p. 7457-7466, Vol. 83, No. 15
0022-538X/09/$08.00+0     doi:10.1128/JVI.00285-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Michael J. Lace,1,2* Christina Isacson,3 James R. Anson,1 Attila T. Lörincz,4 Sharon P. Wilczynski,5 Thomas H. Haugen,1,2 and Lubomír P. Turek1,2

Veterans Affairs Medical Center,1 Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242,2 Virginia Mason Medical Center, Seattle, Washington 98101,3 Wolfson Institute of Preventive Medicine, London EC1M 6BQ, United Kingdom,4 City of Hope Medical Center, Duarte, California 910105

Received 9 February 2009/ Accepted 12 May 2009

Human papillomavirus (HPV) DNAs isolated from cervical and head and neck carcinomas frequently contain nucleotide sequence alterations in the viral upstream regulatory region (URR). Our study has addressed the role such sequence changes may play in the efficiency of establishing HPV persistence and altered keratinocyte growth. Genomic mapping of integrated HPV type 16 (HPV-16) genomes from 32 cervical cancers revealed that the viral E6 and E7 oncogenes, as well as the L1 region/URR, were intact in all of them. The URR sequences from integrated and unintegrated viral DNA were found to harbor distinct sets of nucleotide substitutions. A subset of the altered URRs increased the potential of HPV-16 to establish persistent, cell growth-altering viral-genome replication in the cell. This aggressive phenotype in culture was not solely due to increased viral early gene transcription, but also to augmented initial amplification of the viral genome. As revealed in a novel ori-dependent HPV-16 plasmid amplification assay, the altered motifs that led to increased viral transcription from the intact genome also greatly augmented HPV-16 ori function. The nucleotide sequence changes correlate with those previously described in the distinct geographical North American type 1 and Asian-American variants that are associated with more aggressive disease in epidemiologic studies and encompass, but are not limited to, alterations in previously characterized sites for the negative regulatory protein YY1. Our results thus provide evidence that nucleotide alterations in HPV regulatory sequences could serve as potential prognostic markers of HPV-associated carcinogenesis.

* Corresponding author. Mailing address: Veterans Affairs Medical Center, 601 Highway 6 West, Iowa City, IA 52246. Phone: (319) 338-0581, ext. 7504. Fax: (319) 339-7178. E-mail: michael-lace{at}uiowa.edu

{triangledown} Published ahead of print on 20 May 2009.

Journal of Virology, August 2009, p. 7457-7466, Vol. 83, No. 15
0022-538X/09/$08.00+0     doi:10.1128/JVI.00285-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lace, M. J., Anson, J. R., Klingelhutz, A. J., Lee, J. H., Bossler, A. D., Haugen, T. H., Turek, L. P. (2009). Human Papillomavirus (HPV) Type 18 Induces Extended Growth in Primary Human Cervical, Tonsillar, or Foreskin Keratinocytes More Effectively than Other High-Risk Mucosal HPVs. J. Virol. 83: 11784-11794 [Abstract] [Full Text]  
  • Lace, M. J., Yamakawa, Y., Ushikai, M., Anson, J. R., Haugen, T. H., Turek, L. P. (2009). Cellular factor YY1 downregulates the human papillomavirus 16 E6/E7 promoter, P97, in vivo and in vitro from a negative element overlapping the transcription-initiation site. J. Gen. Virol. 90: 2402-2412 [Abstract] [Full Text]  


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