This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yang, R.
Right arrow Articles by Roden, R. B. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, R.
Right arrow Articles by Roden, R. B. S.

 Previous Article  |  Next Article 

Journal of Virology, June 2005, p. 6741-6750, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6741-6750.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Papillomavirus Capsid Mutation To Escape Dendritic Cell-Dependent Innate Immunity in Cervical Cancer

Rongcun Yang,1 Cosette M. Wheeler,4 Xiaojiang Chen,5 Satoshi Uematsu,6 Kiyoshi Takeda,6 Shizuo Akira,6 Diana V. Pastrana,7 Raphael P. Viscidi,2 and Richard B. S. Roden1,3*

Departments of Pathology,1 Pediatrics,2 Gynecology & Obstetrics, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205,3 University of New Mexico Department of Molecular Genetics and Microbiology, Albuquerque, New Mexico 87131,4 Department of Biochemistry and Molecular Genetics, University of Colorado Health Science Center, School of Medicine, Denver, Colorado 80262,5 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan,6 Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland 208927

Received 24 November 2004/ Accepted 18 January 2005

Infection with oncogenic human papillomaviruses (HPVs), typified by HPV type 16 (HPV16), is a necessary cause of cervical cancer. Prophylactic vaccination with HPV16 L1 virus-like particles (VLPs) provides immunity. HPV16 VLPs activate dendritic cells and a potent neutralizing immunoglobulin G (IgG) response, yet many cervical cancer patients fail to generate detectable VLP-specific IgG. Therefore, we examined the role of the innate recognition of HPV16 L1 in VLP-induced immune responses and its evasion during carcinogenesis. Nonconservative mutations within HPV16 L1 have been described in isolates from cervical cancer and its precursor, high-grade cervical intraepithelial neoplasia (CIN). We determined the effect of mutations in L1 upon in vitro self-assembly into VLPs and their influence upon the induction of innate and adaptive immune responses in mice. Several nonconservative mutations in HPV16 L1 isolated from high-grade CIN or cervical carcinoma prevent self-assembly of L1 VLPs. Intact VLPs, but not assembly-defective L1, activate dendritic cells to produce proinflammatory factors, such as alpha interferon, that play a critical role in inducing adaptive immunity. Indeed, effective induction of L1-specific IgG1 and IgG2a was dependent upon intact VLP structure. Dendritic cell activation and production of virus-specific neutralizing IgG by VLPs requires MyD88-dependent signaling, although the L1 structure that initiates MyD88-mediated signaling is distinct from the neutralizing epitopes. We conclude that innate recognition of the intact L1 VLP structure via MyD88 is critical in the induction of high-titer neutralizing IgG. Tumor progression is associated with genetic instability and L1 mutants. Selection for assembly-deficient L1 mutations suggests the evasion of MyD88-dependent immune control during cervical carcinogenesis.

* Corresponding author. Mailing address: Ross Research Building, Room 512B, The Johns Hopkins School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205. Phone: (410) 502-5161. Fax: (443) 287-4295. E-mail: roden{at}jhmi.edu.

Journal of Virology, June 2005, p. 6741-6750, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6741-6750.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Senger, T., Becker, M. R., Schadlich, L., Waterboer, T., Gissmann, L. (2009). Identification of B-Cell Epitopes on Virus-Like Particles of Cutaneous Alpha-Human Papillomaviruses. J. Virol. 83: 12692-12701 [Abstract] [Full Text]  
  • Griesser, H., Sander, H., Walczak, C., Hilfrich, R. A. (2009). HPV Vaccine Protein L1 Predicts Disease Outcome of High-Risk HPV+ Early Squamous Dysplastic Lesions. Am J Clin Pathol 132: 840-845 [Abstract] [Full Text]  
  • Conway, M.J., Meyers, C. (2009). Replication and Assembly of Human Papillomaviruses. JDR 88: 307-317 [Abstract] [Full Text]  
  • Chen, Z., DeSalle, R., Schiffman, M., Herrero, R., Burk, R. D. (2009). Evolutionary Dynamics of Variant Genomes of Human Papillomavirus Types 18, 45, and 97. J. Virol. 83: 1443-1455 [Abstract] [Full Text]  
  • Chan, J. K., Berek, J. S. (2007). Impact of the Human Papilloma Vaccine on Cervical Cancer. JCO 25: 2975-2982 [Abstract] [Full Text]  
  • Hasan, U. A., Bates, E., Takeshita, F., Biliato, A., Accardi, R., Bouvard, V., Mansour, M., Vincent, I., Gissmann, L., Iftner, T., Sideri, M., Stubenrauch, F., Tommasino, M. (2007). TLR9 Expression and Function Is Abolished by the Cervical Cancer-Associated Human Papillomavirus Type 16. J. Immunol. 178: 3186-3197 [Abstract] [Full Text]  
  • Lipke, M. M. (2006). An Armamentarium of Wart Treatments. Clin Med Res 4: 273-293 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»