MRC National Institute for Medical Research, London
Science for Health
Structural analysis identifies a human papillomavirus-encoded amyloid protein
30 July 2008
Human papillomaviruses (HPV) are the primary cause of cervical cancer, with over half of all cases being caused by HPV type 16. Cervical cancer affects around 500,000 women each year and is responsible for approximately 250,000 deaths, mainly in developing countries that lack cervical screening and vaccination programmes. High-risk human papillomavirus infections are however very common, with cervical cancer usually developing from areas of low-grade disease in women who are persistently infected. Considerable effort at present is focused on understanding the biology of infection and the mechanisms of disease progression.
It has been known for some time that infection of the cervix by HPV 16 is associated with abundant expression of one of the virally-encoded proteins known as E1^E4. E1^E4 interacts with the cellular cytoskeleton and is thought to change the structure of the cell in order to allow efficient virus production and escape. The reasons for the massive abundance of E1^E4 and the mechanism by which it disrupts cellular integrity was not previously well understood. As part of a collaboration led by Pauline McIntosh and John Doorbar (pictured) in the Division of Virology in conjunction with Stephen Martin and John Eccleston in the Division of Physical Biochemistry, it has been shown for the first time that the E1^E4 protein of HPV 16 has an amyloid-fibre form that explains many of its functional characteristics. Amyloid formation not only explains how E1^E4 can become so abundant, but also provides new insight into the way that E1^E4 can cross-link the cellular cytoskeleton and interfere with normal cell structure.
Amyloid-fibre formation in diseases such as Alzheimer's is usually detrimental to the cell, and this is likely also to be the case following E1^E4 expression in the cervix. It appears however that amyloid formation offers an advantage to the virus, by disrupting the integrity of the infected epithelial cell and allowing efficient virus transfer and possibly other functions. One practical application of this work is in cervical diagnosis. The very high abundance of E1^E4 allows it to serve as a marker of infection, and when combined with established markers of cell proliferation, enables the severity of cervical neoplasia to be assessed. It is hoped that amyloid imaging probes may be used in improved screening regimes in order to more reliably identify early cervical disease.
The article was published in the Journal of Virology and was selected by the editors to feature in the Spotlight section as an article of significant interest.
Original article
The research findings are published in full in:
Pauline B. McIntosh, Stephen R. Martin, Deborah J. Jackson, Jameela Khan, Erin R. Isaacson, Lesley Calder, Kenneth Raj, Heather M. Griffin, Qian Wang, Peter Laskey, John F. Eccleston, and John Doorbar
Structural Analysis Reveals an Amyloid Form of the HPV 16 E1^E4 Protein and Provides a Molecular Basis for its Accumulation
Journal of Virology, 82, 8196-8203. Pubmed abstract
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