Approximately 3.7 billion people worldwide — or 67 percent of Earth’s population — under the age of 50 are infected with the herpes simplex virus type one, which is known to cause cold sores around the mouth, according to the World Health Organization. An additional 417 million — roughly 11 percent of the global population — are estimated by the WHO to be infected with HSV-2, the sexually transmitted form of herpes.

Senior Madison Frame worked at Van Andel Research Institute over the summer to determine some of the proteins that may be involved in the process of cellular infection for HSV-2. She focused on several protein kinases, which is a group of proteins that add phosphate groups to other proteins in the cell. This chemical modification can be part of a chain of protein signals that initiate different processes in the cell.

Frame’s work focused on identifying human proteins that the virus uses to infect cells, rather than the viral proteins themselves.

“We were specifically targeting certain human kinases that the virus uses to travel from the edge of the cell to the nucleus, where it replicates,” Frame said.

Her research in the Triezenberg lab, part of the institute’s Center for Epigenetics, focused on whether several kinases that were found to be important in HSV-1 infections were also important in HSV-2 infections. Doing so could help researchers develop treatments to manage symptoms or prevent further transmission of the virus.

The Triezenberg lab where Frame worked over the summer focuses on researching the herpes virus, although Frame said the larger body of research on herpes has focused on HSV-1, not HSV-2.

“We had done experiments a little while back asking which of the many human kinases are important for early steps of infection by HSV-1, and through the years and the various experiments we did, we had narrowed it down to two or three that we thought were really important,” said Steven Triezenberg, president and dean of Van Andel Institute Graduate School and head of the lab where Frame worked. “Madison asked whether those two or three kinases were also important in early steps of HSV-2 infection. Her results told us that one of them still seems to be important, but the other two, not so much, and that was kind of a surprise for us.”

Understanding how the virus uses cellular processes for its own survival and reproduction will help researchers develop treatments for herpes viruses, according to Tatiana Coverdell ’17, who also worked as a research intern in the Triezenberg lab. Once researchers identify the important cellular factors, they can develop targeted treatments to work against the virus.

“There are basically two goals: part of it was just looking at different parts of the replication cycle and trying to understand how the virus and cell interact, and then another part of it was testing how these inhibitors worked in preventing viral replication and infection,” Coverdell said.

Currently, there are few treatment methods available to treat the symptoms of herpes infections, Frame said. Even though an infected person may not always exhibit symptoms, the infection lasts for a lifetime, remaining present in facial nerve cells. Drugs that prevent the virus from infecting cells can help prevent the transmission and spread of the virus.

Frame studied several kinases that researchers had previously found to be important in preventing HSV-1 infection. She treated cultures of cells with drugs to inhibit either of the kinases and then attempted to infect the cells with HSV-2.

Based on whether the virus successfully infected and replicated in the cells, Frame was able to distinguish whether those kinases were needed for the virus to travel from the edge of the cell to the nucleus, where it would replicate.

“A lot of the research right now is kind of done assuming that a lot of the work done for HSV-1 will also apply to HSV-2,” Frame said. “A lot of the work done in the Triezenberg lab suggests that’s not the case, and that there are a lot of subtle differences that lead to differences in how you would treat the two different infections.”

She found that one of the kinases involved was also important for the HSV-2 infection process but was not involved with the pathway the researchers expected, suggesting that the kinase may be involved in a different pathway that is important for viral infection.

“That opens up two possibilities for us,” Triezenberg said. “One, that her experiments suggest there’s a new pathway we didn’t know about — that’s always exciting — and the second is that there’s something about those experiments that gave us an incorrect answer. That’s where we need to focus more carefully: Can we really validate the results Madison’s experiment seems to be giving us, that this kinase is important, but not in the pathways we know about?”

Although the researcher team needs to do more work to determine which of these scenarios is true, Triezenberg said Frame’s research may have identified a new pathway that future anti-viral treatments could target.

“The work that she did really helps move us along,” Triezenberg said. “There are ideas that come out of her work that might suggest that we could find drugs that might work for one virus or the other. Nowadays, for a drug to be approved, you have to know how a drug works, and that second question Madison left us with is how it works. It means there’s a lot more work to be done yet before we could be confident in moving this forward for drug discovery.”

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