By Michele Sequeira

Viral Trojan Horses

UNM Scientists Believe HPV Viruses Trick Their Way Inside Cells

University of New Mexico cancer researcher Michelle Ozbun's willingness to explore the unknown helps explain why she enjoys the process of scientific discovery.

"We have no idea what we're going to find out," says Ozbun, the Maralyn S. Budke Endowed Professor of Viral Oncology at the UNM Comprehensive Cancer Center. She was recently awarded two grants to study various aspects of human papillomavirus (HPV) infection, which has been linked to cervical, vaginal, vulvar and some types of throat cancer.

Ozbun is among a handful of international experts who study HPV and its effect on cells and people. HPV, like all viruses, cannot reproduce on its own, so a virus particle must get inside a cell and use the cell's equipment to make more virus particles.

Her two-year, $960,000 grant from Johnson & Johnson will focus on the process HPV uses to infect cells. Her five-year, $1.7 million grant from the National Institutes of Health will focus on epithelial growth factor receptor and how it tells the cell to take in a virus.

The grants focus on basic science, but Ozbun and her team also hope to develop new methods for measuring infections. Both areas of research could prove useful in, for example, finding better ways to sterilize medical devices or new treatments for people who are already infected with HPV.

"It's hard to predict," says Ozbun of her research interests. "That's the cool part about it."

Ozbun suspects viruses are taking advantage of endocytosis - the process cells use to take in nutrients and other molecules from their surroundings - to sneak inside. "Nobody knows what receptor or receptors the virus binds to that tell the cell to start the endocytosis process," she says.

She and her research team have a strong guess. They have shown that HPV virus particles bind to the surface of skin cells and to molecules in the extracellular matrix, a scaffolding that surrounds the cells and gives tissue its structure. But, to cause an infection, the virus still needs to get inside a skin cell.

Cells constantly receive chemical signals from the extracellular matrix in the form of molecules that attach to receptors on the cell surface, she explains. This touches off a cascade of chemical changes within the cell that sometimes cause the cell to take in the receptor and whatever is attached to it.

Ozbun thinks HPV hijacks this process. She theorizes that virus particles attach to electrically charged extracellular matrix molecules that also hold epithelial growth factors (EGFRs). When these molecules attach to EGFRs on a cell's surface, the cell takes these molecules in - and the attached HPV virus particles along with them.

"So the virus is just piggybacking on these normal processes," Ozbun says. "It's like a Trojan Horse. It would be really hard to help the cell differentiate [the HPV virus particle]."

To test this theory, the Ozbun team is creating new measurement methods. One will help them to see cells that are producing HPV ribonucleic acid (RNA), which carries instructions for making proteins to the structures in the cell that make them. Cells infected with HPV would produce RNA that encodes for HPV proteins.

Ozbun and her team can use special microscopes to identify HPV RNA. "It works as proof-of-concept right now," she says. They hope to program software that will measure how many cells are infected and how much HPV RNA each cell has.

She is also collecting skin and other samples from people infected with HPV. This will allow her team to compare how HPV grown in a lab may behave differently from HPV that passes between humans.

And, Ozbun hopes that learning the fundamentals of the infection process will lead to treatments, new ways to prevent infections - and uses she can't even imagine yet.

Categories: Comprehensive Cancer Center, Research