Structural Biologists Seek to Understand How Viruses and Cells Interact By Cindy Spence
For the billions of viral particles that populate our bodies, the connections they make with host cells can be the difference between sickness and health.
Mavis Agbandje-McKenna has spent much of her career seeking to understand those connections and manipulate them, either to prevent disease or cure it.
“Viruses can infect you and do nothing, they can infect you and have minor effects, or they can kill you,” says Agbandje-McKenna, director of UF’s Center for Structural Biology.
As a structural virologist, Agbandje-McKenna uses X-ray crystallography and cryo-electron microscopy to “see” viruses just 20 billionths of a meter in diameter in three dimensions and observe how they use protrusions of proteins on their surface to attach to a cell.
Viruses are not “alive” in the classic sense and cannot replicate their own genetic material. They must commandeer a cell’s machinery to replicate their own DNA or RNA, creating new viral particles that then exit and move on to the next cell, spreading infection.
And the interplay between proteins on the surface of the cell and the invading virus can be the difference between a virus that is benign and one that is lethal.
“One or two amino acids out of over 500 will lead to a virus that either kills, or doesn’t kill,” says Agbandje-McKenna. “So, then, my question is where are those differences located, and what is it that they are doing that enables them to have this very disparate difference in phenotype.”
The average person probably sees all viruses as bad, but medical researchers have used benign viruses for years to deliver corrective genes from one organism to another.
For example, University of Florida researchers were pioneers in using the adeno-associated virus, or AAV, as a vector to ferry therapeutic genes to different parts of the body to treat diseases such as blindness and cystic fibrosis.
But Agbandje-McKenna says more than half the population has been exposed to AAVs and developed an immunity that would preclude AAV-based vectors from delivering their repair gene to the target.
Using what she’s learned about the structure of viruses and their host cells, Agbandje-McKenna is working to understand where antibodies bind to these viruses, so she can use molecular biology to change the connection point just enough to fool the body.
“Then I can use the virus as a gene delivery vector,” Agbandje-McKenna says. “It’s as if my body hasn’t seen that virus before, because I’ve changed the site where that antibody would normally bind.”
Many viruses are adaptable and can mutate quickly, producing different strains. Influenza, for example, is so adaptable that the flu vaccine changes year to year.
“The only time you get a new cold is if you haven’t seen that strain before. If you’ve seen it, and survived it, you’ve created antibodies, so the next time you see it, those antibodies will stop that virus from causing disease,” Agbandje-McKenna says.
Another challenge is that, just like their more virulent cousins, some benign viruses infect the lungs better, some infect the eyes better, others infect the liver or the kidneys better. They establish a specialty, so to speak, so using a virus whose specialty is infecting the liver to deliver a gene to treat lung disease is not very effective, says Agbandje-McKenna.
“What is it that allows them to establish different niches in different tissues,” says Agbandje-McKenna. “If I understand that, I know which virus can be tailored for treating different diseases in different organs.”
Agbandje-McKenna has done just that to develop a gene therapy treatment for Duchenne muscular dystrophy, a rare strain of muscular dystrophy that affects only boys and is almost always fatal before patients reach their mid-20s. She took two viruses with known structures and combined them to create a new organism called AAV 2.5. The treatment is currently undergoing clinical trials at the University of North Carolina.
Agbandje-McKenna is also investigating how to use some virus’s affinity for cancer cells to pinpoint delivery of chemotherapy drugs. She is working to understand how a virus, currently in clinical trials for brain and spine tumors known as glioblastoma multiforme, is able to target these cancer cells and not normal cells. She plans to use this information to improve specific tissue targeting by other viruses.
Understanding structure also is important in viruses that cause illness. Agbandje-McKenna is particularly interested in parvoviruses, such as human bocavirus, a cause of respiratory infections, and parvovirus B19, which causes Fifth Disease, the fifth most common childhood disease.
Fifth Disease, a rash, is rampant in day care centers and other places children congregate. While it is not generally fatal to children, it can cause problems for pregnant women.
“We see it in places where children are, and that’s actually more dangerous, because that is where you’re going to find pregnant women, and if they get it, the fetus can be aborted,” says Agbandje-McKenna.
It’s hard to imagine a more unlikely path to science and the University of Florida than the one Agbandje-McKenna has followed. Born in Nigeria, she was living with her grandmother when civil war broke out in her country in the late 1960s and more than two million people died from violence or famine. Agbandje-McKenna was able to escape and moved to London to join her parents when she was 11 years old.
One day, when she feels it is safe, she would like to take her two children and her husband to Nigeria, to meet her aunts and uncles and see her heritage.
“Most days, I visualize it, I can see it. I was old enough when I left to remember, so I can see it in my head and kind of relive it, very often actually,” says Agbandje-McKenna. “One day I would like to go back.”
She earned a Ph.D. in chemistry from the University of London, where she met her husband and research partner, UF molecular biologist Robert McKenna. Like many couples in science fields, they looked for two jobs in the same location when they came to the United States for postdoctoral work. They found that at Purdue University, where Agbandje-McKenna learned X-ray crystallography, a skill that shifted her work from pure chemistry to structural virology.
She says her chemistry background is helpful, and the opportunity to work with her husband has been rewarding. When they arrived at UF in 1999 they shared a lab at the McKnight Brain Institute until their operation needed more space. Between the two of them, they supervise at least a dozen students at a time and even though their labs are now separate, they share the workload.
“We help supervise each other’s students,” Agbandje-McKenna says. “If I’m not there, he’s there, and if he’s not there, I’m there. It’s a very student-centric lab, and we like the training, and the energy the students have.”
Shweta Kailasan, a five-year veteran of the lab who expects to get her Ph.D. this summer, says her foundation in structural biology is solid because of Agbandje-McKenna’s training.
“When you leave here as an independent researcher you want to be able to conduct experiments by yourself, independently, and be able to design them rationally,” Kailasan said. “I can do that because of her mentorship.”
Kailasan has played a major role in the bocavirus research, solving the structure of several bocaviruses and enabling development of a peptide that could generate an immune response and perhaps lead to a vaccine.
In 2012, Agbandje-McKenna joined the Microbiology and Infectious Diseases Subcommittee of the National Advisory Allergy and Infectious Diseases Council at the National Institutes of Health, a plum assignment that gives her an early look at the latest work in her field. She sits on a panel that reviews grant proposals and decides which to fund — which helps her, and UF, in multiple ways.
“This allows me to know what the virology community is thinking, and I get to see the sorts of projects that come to the top of the list. That helps me write my grants and helps me advise junior faculty on how to get their grants funded,” says Agbandje-McKenna. “That’s very, very good for me, and it’s information I can bring to UF, to my department or anyone else I’m mentoring. And it’s good visibility for UF.”
Agbandje-McKenna says she likes to stay focused on the how and why of the viral world, letting tech transfer and patents “just happen.” Still, she is happy to advise on translating research to the world at large, and she has a research agreement with AGTC, a local biotech company, and is on the scientific advisory board for Voyager Therapeutics Inc., which works on vector development for brain diseases.
“The people in biotech realize that what we do at the basic science level is important for making translational steps,” says Agbandje-McKenna.
“Discovering cures is what I want, but I want it done right. I don’t want to rush; I don’t like to jump ahead without understanding the fundamentals. I’m very basic science oriented. I want to be able to see the structure, and after seeing it, understand how it does what it does. If you understand that, the rest of it comes.”