BioWorld International Correspondent
LONDON - The nature of the "invisibility cloak" that papillomaviruses throw around themselves in order to escape the attention of the immune system has been elucidated by a team of researchers in Glasgow, Scotland.
Saveria Campo and her colleagues at the Glasgow University Veterinary School have shown that a viral protein produced in cells infected with papillomavirus suppresses the cells' ability to transport molecules of the major histocompatibility complex (MHC) class I to the surface.
Campo, professor of viral oncology at the Institute of Comparative Medicine, told BioWorld International, "Virologists have always wondered why this virus is so poorly seen by the immune system, which makes no antibodies against it and develops no immune cells which recognize it. But now we know. The MHC class I complex presents antigens to the immune system, but it can only do that if it is on the surface of the cell. The viral protein E5 causes it to remain trapped inside the cell, in the Golgi apparatus."
For Campo, the intriguing question that remains to be answered is what happens when the E5 protein is inhibited. "Does this mean that you will get MHC class I back on the cell surface? This would be the way to make the immune system aware that there is an infected cell, which needs to be destroyed," she said.
The researchers have no link to any biotechnology company on the project, but are interested in hearing from potential partners. Their work is published in the Nov. 7, 2002, issue of Oncogene in a paper titled, "The bovine papillomavirus oncoprotein E5 retains MHC class I molecules in the Golgi apparatus and prevents their transport to the cell surface."
There are more than 70 types of human papillomavirus, but only some - mainly types 16 and 18 - are linked to cervical and vulval cancer. About 3,200 women are diagnosed with cervical cancer each year in the UK. Researchers at Cancer Research UK, the UK's largest cancer research charity which, together with the Medical Research Council, funded Campo's work, have shown that about 99 percent of biopsies from women with cervical cancer contain human papillomavirus, particularly types 16 and 18.
Cancer of the vulva is much less common. The virus is thought to be responsible for up to 50 percent of those cancers.
Although the research reported in Oncogene focuses on bovine papillomavirus, initial experiments conducted by Campo and her team have shown that human papillomavirus type 16 shares the same mechanism.
The researchers compared the expression of MHC class I molecules in cells in tissue culture. Cells that expressed viral proteins, but not E5, correctly synthesized and processed MHC class I proteins. But cells that expressed only E5 or that expressed viral proteins including E5 had no MHC class I molecules on their surfaces.
Campo said, "We know that E5 shields the infected cell from attack by the immune system on many different levels. What this paper shows is that E5 stops MHC class I from moving from the center of the cell to the cell surface. Instead, it remains trapped inside the Golgi apparatus."
Experiments carried out by the group showed that the Golgi apparatus of cells infected with E5 contained MHC class I molecules, and further studies showed that these were present in the same locations as E5. The group suggested that E5 causes retention of the MHC class I complex within the Golgi apparatus by increasing the pH there.
They note that the failure of the cell to transport MHC class I molecules to its surface cannot be due to a generalized disturbance of intracellular transportation, as they have already shown that transport of other molecules within the cell is not affected by the presence of E5.
Next, apart from pursuing ways of inhibiting E5, Campo wants to explore further the molecular mechanisms that allow E5 and other proteins of papillomaviruses to transform cells so that they proliferate.