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

 Previous Article  |  Next Article 

Journal of Virology, October 2003, p. 10186-10201, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10186-10201.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Organization of Human Papillomavirus Productive Cycle during Neoplastic Progression Provides a Basis for Selection of Diagnostic Markers

National Institute for Medical Research, Mill Hill, London,¹ MRC Centre for Protein Engineering,² MRC Cancer Cell Unit, Cambridge,⁶ Department of Histopathology, Queens Medical Centre, Nottingham, United Kingdom,⁵ Institute for Pathology, University of Tubingen, Tubingen, Germany,³ McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin,⁴ University of Otago, Dunedin, New Zealand⁷

Received 21 March 2003/ Accepted 12 June 2003

The productive cycle of human papillomaviruses (HPVs) can be divided into discrete phases. Cell proliferation and episomal maintenance in the lower epithelial layers are followed by genome amplification and the expression of capsid proteins. These events, which occur in all productive infections, can be distinguished by using antibodies to viral gene products or to surrogate markers of their expression. Here we have compared precancerous lesions caused by HPV type 16 (HPV16) with lesions caused by HPV types that are not generally associated with human cancer. These include HPV2 and HPV11, which are related to HPV16 (supergroup A), as well as HPV1 and HPV65, which are evolutionarily divergent (supergroups E and B). HPV16-induced low-grade squamous intraepithelial lesions (CIN1) are productive infections which resemble those caused by other HPV types. During progression to cancer, however, the activation of late events is delayed, and the thickness of the proliferative compartment is progressively increased. In many HPV16-induced high-grade squamous intraepithelial lesions (CIN3), late events are restricted to small areas close to the epithelial surface. Such heterogeneity in the organization of the productive cycle was seen only in lesions caused by HPV16 and was not apparent when lesions caused by other HPV types were compared. By contrast, the order in which events in the productive cycle were initiated was invariant and did not depend on the infecting HPV type or the severity of disease. The distribution of viral gene products in the infected cervix depends on the extent to which the virus can complete its productive cycle, which in turn reflects the severity of cervical neoplasia. It appears from our work that the presence of such proteins in cells at the epithelial surface allows the severity of the underlying disease to be predicted and that markers of viral gene expression may improve cervical screening.

This article has been cited by other articles:

• McIntosh, P. B., Martin, S. R., Jackson, D. J., Khan, J., Isaacson, E. R., Calder, L., Raj, K., Griffin, H. M., Wang, Q., Laskey, P., Eccleston, J. F., Doorbar, J. (2008). Structural Analysis Reveals an Amyloid Form of the Human Papillomavirus Type 16 E1{wedge}E4 Protein and Provides a Molecular Basis for Its Accumulation. J. Virol. 82: 8196-8203 [Abstract] [Full Text]  
• Nafz, J., Kohler, A., Ohnesorge, M., Nindl, I., Stockfleth, E., Rosl, F. (2007). Persistence of Mastomys natalensis papillomavirus in multiple organs identifies novel targets for infection. J. Gen. Virol. 88: 2670-2678 [Abstract] [Full Text]  
• Dillon, S., Sasagawa, T., Crawford, A., Prestidge, J., Inder, M. K., Jerram, J., Mercer, A. A., Hibma, M. (2007). Resolution of cervical dysplasia is associated with T-cell proliferative responses to human papillomavirus type 16 E2. J. Gen. Virol. 88: 803-813 [Abstract] [Full Text]  
• Michel, A., Kopp-Schneider, A., Zentgraf, H., Gruber, A. D., de Villiers, E.-M. (2006). E6/E7 Expression of Human Papillomavirus Type 20 (HPV-20) and HPV-27 Influences Proliferation and Differentiation of the Skin in UV-Irradiated SKH-hr1 Transgenic Mice. J. Virol. 80: 11153-11164 [Abstract] [Full Text]  
• Kraus, I., Molden, T., Holm, R., Lie, A. K., Karlsen, F., Kristensen, G. B., Skomedal, H. (2006). Presence of E6 and E7 mRNA from Human Papillomavirus Types 16, 18, 31, 33, and 45 in the Majority of Cervical Carcinomas. J. Clin. Microbiol. 44: 1310-1317 [Abstract] [Full Text]  
• Collins, A. S., Nakahara, T., Do, A., Lambert, P. F. (2005). Interactions with Pocket Proteins Contribute to the Role of Human Papillomavirus Type 16 E7 in the Papillomavirus Life Cycle. J. Virol. 79: 14769-14780 [Abstract] [Full Text]  
• Nakahara, T., Peh, W. L., Doorbar, J., Lee, D., Lambert, P. F. (2005). Human Papillomavirus Type 16 E1{wedge}E4 Contributes to Multiple Facets of the Papillomavirus Life Cycle. J. Virol. 79: 13150-13165 [Abstract] [Full Text]  
• Wilson, R., Fehrmann, F., Laimins, L. A. (2005). Role of the E1{wedge}E4 Protein in the Differentiation-Dependent Life Cycle of Human Papillomavirus Type 31. J. Virol. 79: 6732-6740 [Abstract] [Full Text]  
• Davy, C. E., Jackson, D. J., Raj, K., Peh, W. L., Southern, S. A., Das, P., Sorathia, R., Laskey, P., Middleton, K., Nakahara, T., Wang, Q., Masterson, P. J., Lambert, P. F., Cuthill, S., Millar, J. B. A., Doorbar, J. (2005). Human Papillomavirus Type 16 E1{wedge}E4-Induced G2 Arrest Is Associated with Cytoplasmic Retention of Active Cdk1/Cyclin B1 Complexes. J. Virol. 79: 3998-4011 [Abstract] [Full Text]  
• Raj, K., Berguerand, S., Southern, S., Doorbar, J., Beard, P. (2004). E1{wedge}E4 Protein of Human Papillomavirus Type 16 Associates with Mitochondria. J. Virol. 78: 7199-7207 [Abstract] [Full Text]  
• Peh, W. L., Brandsma, J. L., Christensen, N. D., Cladel, N. M., Wu, X., Doorbar, J. (2004). The Viral E4 Protein Is Required for the Completion of the Cottontail Rabbit Papillomavirus Productive Cycle In Vivo. J. Virol. 78: 2142-2151 [Abstract] [Full Text]  
• Wang, Q., Griffin, H., Southern, S., Jackson, D., Martin, A., McIntosh, P., Davy, C., Masterson, P. J., Walker, P. A., Laskey, P., Omary, M. B., Doorbar, J. (2004). Functional Analysis of the Human Papillomavirus Type 16 E1{wedge}E4 Protein Provides a Mechanism for In Vivo and In Vitro Keratin Filament Reorganization. J. Virol. 78: 821-833 [Abstract] [Full Text]