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* International Agency for Research on Cancer-World Health Organization, Lyon, France;
Bayer BioScience, Brussels, Belgium;
Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama, Japan;
Institut National de la Santé et de la Recherche Médicale Unité 271, Lyon, France;
¶ Deutsches Krebsforschungszentrum, Heidelberg, Germany;
|| Institut für Medizinische Virologie, Forschungssektion Experimentelle Virologie, Tübingen, Germany; and
# Istituto Europeo di Oncologia, Milan, Italy
Cervical cancer development is linked to the persistent infection by high-risk mucosal human papillomaviruses (HPVs) types. The E6 and E7 major oncoproteins from this dsDNA virus play a key role in the deregulation of the cell cycle, apoptosis, and adaptive immune surveillance. In this study, we show for the first time that HPV type 16 (HPV16), the most carcinogenic type among the high-risk subgroup, interferes with innate immunity by affecting the expression of TLRs. Infection of human primary keratinocytes with HPV16 E6 and E7 recombinant retroviruses inhibits TLR9 transcription and hence functional loss of TLR9-regulated pathways. Similar findings were achieved in HPV16-positive cancer-derived cell lines and primary cervical cancers, demonstrating that this event occurs also in an in vivo context. Interestingly, E6 and E7 from the low-risk HPV type 6 are unable to down-regulate the TLR9 promoter. In addition, E6 and E7 from the high-risk HPV type 18, which are known to persist less competently in the host than HPV16, have reduced efficiency compared with HPV16 in inhibiting TLR9 transcription. Furthermore, a CpG motif derived from the HPV16 E6 DNA sequence activated TLR9, indicating this virus is able to initiate innate responses via the receptor it later down-regulates. This study reveals a novel mechanism used by HPV16 to suppress the host immune response by deregulating the TLR9 transcript, providing evidence that abolishing innate responses may be a crucial step involved in the carcinogenic events mediated by HPVs.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The study was supported by grants from La Ligue Contre le Cancer (Comité de la Savoie), "Applied Tumour Virology" German-French cooperation, and Deutsches Krebsforschungszentrum-Cancéropôle du Grand-Est.
2 Address correspondence and reprint requests to Dr. Uzma A. Hasan, Infections and Cancer Biology Group, International Agency for Research on Cancer-World Health Organization, 150 Cours Albert-Thomas, 69372 Lyon Cedex 08, France. E-mail address: hasan{at}iarc.fr
3 Abbreviations used in this paper: HPV, human papillomavirus; CIN, cervical intraepithelial neoplasia; HPK, human primary keratinocyte; HR, high risk; LC, Langerhans cell; LR, low risk; VLP, virus-like particle.
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  A. P. Lepique, K. R. P. Daghastanli, I. M. Cuccovia, and L. L. Villa HPV16 Tumor Associated Macrophages Suppress Antitumor T Cell Responses Clin. Cancer Res., July 1, 2009; 15(13): 4391 - 4400. [Abstract] [Full Text] [PDF]
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 H. Echchannaoui, M. Bianchi, D. Baud, M. Bobst, J.-C. Stehle, and D. Nardelli-Haefliger Intravaginal Immunization of Mice with Recombinant Salmonella enterica Serovar Typhimurium Expressing Human Papillomavirus Type 16 Antigens as a Potential Route of Vaccination against Cervical Cancer Infect. Immun., May 1, 2008; 76(5): 1940 - 1951. [Abstract] [Full Text] [PDF]
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