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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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