Research highlight: Dr. Haidong Gu

Study of how virus overcomes body's defenses may lead to "New era for antiviral drug design"
 
For such simple things – just tiny packages of genetic material – viruses are amazingly effective at getting past the human body’s quite extraordinary defense system and infecting cells. In addition, viruses can also mutate very quickly, which makes them difficult targets for even the most advanced virus-fighting drugs. One researcher in the WSU Department of Biological Sciences is studying the cell’s front-line antiviral strategy and how viruses are able to shut it down. What she is learning may show a new vulnerability that drug designers can exploit to fight viruses, and greatly diminish the challenges posed by mutation.
 
“When a virus infects the body and invades an individual cell, the cell senses the viral intrusion and immediately starts to restrict the virus,” says WSU researcher Haidong Gu, associate professor of biological sciences. This cellular-level surveillance is performed by pre-existing molecules, including proteins that have the job of sensing DNA damage or the misplacement of DNA or RNA molecules in the cell. These pre-existing proteins can also instantly spot the viral genome and try to silence them. “What I’ve been doing is trying to find out what cellular factors are doing this surveillance job and how the virus defeats it.”
 
She and her research group have found that viruses make a protein, called infected cell protein 0 (ICP0), which tricks the cell into destroying its own cellsurveillance proteins by making the cell think they are garbage to be purged.
ICP0 does this by labeling the cellsurveillance proteins with the same enzyme (E3 ubiquitin ligase) that the cell itself uses to label unneeded molecules to be removed. As a result, the cell sees its own proteins as garbage and degrades them, leaving the cell unable to detect the virus, Gu describes. The virus can then go about its business: taking over the cell and turning it into a virus-making machine.
 
With that understanding in hand, Gu’s research team sought out more detail. They continued investigating the mechanism using herpes simplex virus-1 as a model virus. “We use herpes simplex virus because it’s easy to grow, and also because it establishes latency,” she said. Almost everyone has been infected with herpes simplex virus, but it usually lies dormant in the body, only manifesting itself — frequently as a cold sore —once in a while. “That tug-of-war between the virus and the body’s immune system on when to reactivate and when to remain latent, can show us a lot about the host-virus interaction,” she remarked.
 
In the study of herpes simplex virus, Gu’s group tracked backward to the gene that makes the cell-surveillance proteins and found that the gene actually makes seven similar-looking proteins (or isoforms), each of which is made up of building blocks called amino acids. The first half (or the N terminus) of each isoform is the same, but the second half (the C terminus) is different, Gu says. “What we found is that two of the isoforms that ICPO targets, which are called PML I and PML II , differ by about 25-30 percent of their C terminus amino acids, and ICP0 can recognize both of them. In fact, when we make little mutations in ICP0, we find that it causes the degradation of one PML target, but not the other, so ICP0 sees PML I and PML II as two different enemies,” she explains.
 
This reveals a possible opening to fight not only herpes simplex virus, but other viruses too, because they all employ similar tactic to circumvent the body’s initial defenses. Currently, Gu says, typical drugs are designed to fight a virus after it has already gotten past the cell’s front-line defenses. Because the viruses are swift to reproduce and mutate, they can develop resistance very quickly to these types of drugs. She adds, “It takes years to get a drug developed, but it can take much less time for the virus to mutate against those drugs.” This can render the drugs too ineffective to be useful.
Instead of this approach, Gu sees a different path forward. “We are looking at how to modulate the host to specifically target the virus. So rather than directly going in and designing a drug to kill the virus, which is what drugs are designed to do today, we want to fine-tune the human response through a more generalized drug. This puts far less pressure on the virus to mutate,” Gu says. She hopes to collaborate with Dr. Ladislau Kovari in the WSU School of Medicine’s Department of Biochemistry and Molecular Biology to get insight into the structure of ICP0, which could inform the design of such a drug.
 
Gu adds, “It’s admittedly a long shot for now, but if things pan out, we  just might be entering a new era for antiviral drug design.”
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Research highlight: Dr. Haidong Gu 11/28/2018
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