Viral Evasion Discovery Points to Potential New Drugs

By Allison Hydzik

Some viruses are evading our immune systems by blocking the protein that our cells use as a “check” to block early stages of growth, thereby allowing the deadly viruses to slip in unnoticed.

The blocking structure, called a “stem-loop,” is found at the beginning of the virus’s genetic material. This discovery, recently published in the journal Science, is the first time researchers have found such an evasion mechanism built directly into the genetic material of a virus.

Credit: Fred Murphy, Sylvia Whitfield/CDC
Scientists have discovered a defense system - built 
into some viruses - that may be vulnerable to treatment. 
The researchers studied alphaviruses similar to the Eastern 
equine encephalitis virus, pictured above in red. This virus 
is transmitted to humans and horses by mosquito bites.
“Knowing how viruses evade the immune system points to a potential target for designing new drugs,” said co-author William Klimstra, Ph.D., associate professor at the University of Pittsburgh’s Center for Vaccine Research. “One of the difficult parts of designing antiviral drugs is making sure the drug targets the virus and not the host, or the drug can cause some very serious side effects. It’s an especially tough nut to crack, making this discovery a very productive area of investigation.”

Senior author Michael Diamond, M.D., Ph.D., a professor of medicine at the Washington University School of Medicine in St. Louis, explained in a press release that by changing a single letter of the virus’s genetic code scientists can disable the stem-loop’s protective effects and allow the virus to be recognized by the host immune protein.

“We hope to find ways to weaken the stem-loop structure with drugs or other treatments, restoring the natural virus-fighting capabilities of the cell and stopping or slowing some viral infections,” he said.

Dr. Klimstra and his colleagues at CVR did much of the virus work for the research in Pitt’s Regional Biocontainment Laboratory, a unique, high-security facility constructed with Pitt and NIH funds.  

The researchers studied alphaviruses, a group of viruses that include West Nile, influenza, SARS, yellow fever and polio. These viruses encode their genes directly into RNA, which is genetic material read by a cell’s protein-making machinery.

When the alphavirus’s stem-loop is stable, a key immune system protein called Ifit1 is blocked from binding to the viral RNA, allowing the virus to begin growing in the cell and enabling infection to proceed unchecked. This builds on several years of research by Dr. Klimstra’s team, including their 2005 discovery showing that Ifit1 has antiviral activity against invading RNA viruses.

“This built-in viral defense mechanism gives us a new opportunity to improve treatment of infection,” said Dr. Diamond. “To control emergent infections, we must continue to look for ways that viruses have antagonized our natural defense mechanisms and discover how to disable them.”

Additional co-authors on this paper include Christina L. Gardener, Ph.D., and Derek W. Trobaugh, Ph.D., both of Pitt’s CVR; Jennifer L. Hyde, Ph.D., James P. White, Ph.D., Gai Liu, Ph.D., and Gaya K. Amarasinghe, Ph.D., all of Washington University; Taishi Kimura, and Kiyoshi Takeda, M.D., Ph.D., both of Osaka University; Cheng Huang, Ph.D., and Slobodan Paessler, D.V.M., Ph.D., both of the University of Texas.

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