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Journal of Virology, April 2009, p. 2907-2916, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02490-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

E7 Oncoprotein of Novel Human Papillomavirus Type 108 Lacking the E6 Gene Induces Dysplasia in Organotypic Keratinocyte Cultures {triangledown}

Rui Jorge Nobre,1,§ Elsa Herráez-Hernández,1 Jian-Wei Fei,1 Lutz Langbein,2 Sylvia Kaden,3 Hermann-Josef Gröne,3 and Ethel-Michele de Villiers1*

Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum, Heidelberg, Germany,1 Division of Skin Carcinogenesis, Deutsches Krebsforschungszentrum, Heidelberg, Germany,2 Department of Cellular and Molecular Pathology, Deutsches Krebsforschungszentrum, Heidelberg, Germany3

Received 4 December 2008/ Accepted 12 January 2009

The genome organization of the novel human papillomavirus type 108 (HPV108), isolated from a low-grade cervical lesion, deviates from those of other HPVs in lacking an E6 gene. The three related HPV types HPV103, HPV108, and HPV101 were isolated from cervicovaginal cells taken from normal genital mucosa (HPV103) and low-grade (HPV108) and high-grade cervical (HPV101) intraepithelial neoplasia (Z. Chen, M. Schiffman, R. Herrero, R. DeSalle, and R. D. Burk, Virology 360:447-453, 2007, and this report). Their unusual genome organization, against the background of considerable phylogenetic distance from the other HPV types usually associated with lesions of the genital tract, prompted us to investigate whether HPV108 E7 per se is sufficient to induce the above-mentioned clinical lesions. Expression of HPV108 E7 in organotypic keratinocyte cultures increases proliferation and apoptosis, focal nuclear polymorphism, and polychromasia. This is associated with irregular intra- and extracellular lipid accumulation and loss of the epithelial barrier. These alterations are linked to HPV108 E7 binding to pRb and inducing its decrease, an increase in PCNA expression, and BrdU incorporation, as well as increased p53 and p21CIP1 protein levels. A delay in keratin K10 expression, increased expression of keratins K14 and K16, and loss of the corneal proteins involucrin and loricrin have also been noted. These modifications are suggestive of infection by a high-risk papillomavirus.

* Corresponding author. Mailing address: Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. Phone: 49-6221-424655. Fax: 49-6221-424822. E-mail: e.devilliers{at}dkfz.de

{triangledown} Published ahead of print on 19 January 2009.

§ Present address: Molecular Pathology Laboratory, Portuguese Institute for Oncology at Coimbra, EPE and Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.

Journal of Virology, April 2009, p. 2907-2916, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02490-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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