Researchers lead the way in important retrovirus research
Penn State researchers and Rebecca Craven, Ph.D., and Leslie Parent, M.D., are involved with separate research projects, but they often find themselves fielding the same question: “Why are you studying a virus that’s only found in chickens?” You might expect two serious researchers to consider it a silly question. But in fact they welcome it, because it gives them an opening to explain their passion for understanding pathogens that cause serious illness in humans.
The retrovirus they’re studying—the Rous sarcoma virus—offers valuable clues into how retroviruses function, both in humans and in animals. For example, the Rous sarcoma virus behaves similarly to human immunodeficiency virus (HIV), which causes AIDS in humans.
“There is a need to better understand the life cycle of retroviruses so we can come up with improved methods for how to short circuit them,” says Craven, associate professor in microbiology and immunology at Penn State College of Medicine. “Rous sarcoma is an interesting virus in its own right because of the disease it causes in birds, but also because it serves as a model system for understanding human pathogens,” she adds.
A benefit to working with Rous sarcoma is that it’s easy to grow in the laboratory and doesn’t require special containment procedures, such as those used for human pathogens like HIV. While it’s easy to use, it provides tremendous insight into most retroviruses and how they function.
Retroviruses such as Rous sarcoma essentially use the cell as a machine to make more virus particles that are spread from cell to cell. A process called reverse transcription takes place and transforms RNA into DNA to alter the composition of the existing cell and new ones that are formed. Although they are studying different aspects of that process, both Craven and Parent are striving to understand how the virus replicates.
Parent and her research team are studying a specific protein called the “gag” protein, which has special signals that allow it to travel to the nucleus of the cell, where it interacts with the cell’s RNA and replicates the virus. Parent’s research is focused on how the gag protein interacts with the host cell.
“The virus has to borrow components that the cell uses for its normal living process,” says Parent, professor at microbiology and immunology at Penn State College of Medicine and chief of the Division of Infectious Diseases and Epidemiology at Penn State Hershey Medical Center. “It tags along with those components to take over the cell, but instead of harming the cell, it uses it to turn out more virus particles.”
While Parent and her team are studying what happens early in the process inside the cell, Craven and her team are evaluating the virus’s structure after it has matured and left the cell. Specifically, the team is studying the capsid protein, which forms a solid shell around newly forms cells and enables them to survive.
Although Parent and Craven are studying different stages of the retrovirus’s development, both have the same end goals: to conduct research that enhances the medical community’s understanding of how a retrovirus functions, and to potentially contribute to the development of new drugs and new ways to battle diseases caused by similar retroviruses in humans. “It is important to understand the basic mechanisms of how viruses interface with cells, because that understanding can lead to new discoveries in cell biology and new targets for anti-viral therapies,” says Parent, who divides her time between research, treating patients, teaching and administrative duties.
“Sometimes researchers don’t think their findings are important when they make them, but then later it turns out that they were very important discoveries,” she adds. “No one can predict when that will happen.”
The discovery of the Rous sarcoma virus was made in 1911 by a researcher named Peyton Rous, who proved that the virus was capable of causing cancer in chickens. Fifty-five years later, Rous won a Nobel Prize for his discovery. Two other Nobel Prizes have been awarded to scientists for their discoveries using the Rous sarcoma virus. In 1975, Howard Temin and David Baltimore won the Nobel Prize for their independent discoveries of the reverse transcription process. And four years later, Harold E. Varmus and J. Michael Bishop won the prize for their discovery that normal genes in chickens could transform into cancerous genes when exposed to the Rous sarcoma virus. “Basic research is a really critical function, because it builds the body of knowledge that will help us stay one step ahead of these viruses and be ready for new diseases that may surface,” Craven says.
Since starting her research twenty years ago, Craven and her team at Penn State have contributed to the science community’s understanding of the intermolecular events that occur to build the shell around maturing cells, and they have increased the science community’s understanding of the principles that determine how a particle matures.
Craven’s lab was one of the first in the country to study retroviruses using an approach called second-site successor. The process used latent viruses that transformed into secondary mutations and corrected the first mutations. The process interfered with virus replication and provided the team with clues into the mechanisms that altered normal cell function.
Today, Craven and her team are utilizing a model system developed by a student to build capsid-like structures in test tubes. The system enables the researchers to make structures that look like particles that would be inside virus cores and to test virus mutations and how they might block the reverse transcription process.
In the past nineteen years, Parent and her team at Penn State have helped shed light on how the gag protein moves into the nucleus, how the retrovirus packages its RNA and, in collaboration with Penn State researcher John Flanagan, Ph.D., determined that the earliest step in the virus assembly is the gag protein’s binding with the RNA.
Parent and her team use microscopy, which fluorescently tags proteins in different colors and enables the researchers to track how the virus proteins move through the cell.
The team also grows live cells in the laboratory, and in its work with Flannigan uses test-tube in vitro methods to study how the virus changes shape when it interacts with the RNA in the nucleus.
Although their projects are focused different stages of the reverse transcription process, the researchers benefit from staying in contact with each other and collaborating with other Penn State researchers in monthly lab meetings.
Both Craven and Parent say Penn State provides the optimum environment for laboratory research because of the lab’s collaboration with physicians as well as with students.
“We’re able to keep the information flowing between clinicians and scientists, and that communication enhances Penn State’s research as well as our patient care,” Parent says. “The open lines of communication between physicians who solely see patients or researchers who solely do experiments enables us to learn from each other and strengthen the jobs we do.”
“Patients also benefit from the fact that we’re a teaching hospital,” she adds. “Our students are young, enthusiastic and hard-working. They broaden our minds and help make this a vibrant place to be doing research and practicing medicine.”