Mimicking viruses may provide new way to defeat them

Viruses, often able to outsmart many of the drugs designed to defeat them, may have met their match, according to new research from the University of Wisconsin-Madison.

The findings show that the introduction of a harmless molecule that uses the same machinery a virus needs to grow may be a potent way to shut down the virus before it infects other cells or becomes resistant to drugs. The results are published in the March issue of the journal, Antimicrobial Agents and Chemotherapy.

“When a virus encounters a susceptible cell, it enters and says, ’I’m now the boss,’” explains John Yin, a UW-Madison associate professor of chemical and biological engineering and senior author of the paper. “It pirates the cell’s resources to produce virus progeny that, following release from the host cell, can infect other cells.”

The current technique to stop a virus in its tracks is to develop drugs that bind to and block the function of virus proteins – molecules the virus produces, with the aid of host cells that help the virus replicate, or make copies of itself. The drugs, says Yin, are like hammers that knock out key functions that the virus uses for growth and reproduction.

But, he points out, this antiviral approach cannot always outsmart the virus: “When a virus reproduces, it doesn’t do so perfectly. Sometimes, it inserts genetic typos, creating variations that may allow some versions of the virus proteins to develop an evolutionary advantage, such as drug resistance.”

While improvements in molecular biology and chemistry have led to new drugs that precisely target virus proteins, they have not been able to stop viruses from producing drug-resistant strains.

“Despite advances in the development of antiviral therapies over the last decade, the emergence and outgrowth of drug-resistant virus strains remains problematic,” says Hwijin Kim, a UW-Madison graduate student in the chemical and biological engineering department, and co-author of the March paper.

Given that drug-resistant virus mutants can arise, Kim and Yin wondered if there might be some antiviral strategies that are harder for a virus to beat. An unexplored approach came to mind.

Rather than designing a drug molecule that inhibits virus proteins, the UW-Madison researchers created a molecule that acts just like the parasitic virus: It enters the cell and hijacks the very machinery the virus requires for its own growth. But unlike the virus, the diversionary molecules are much smaller, meaning they can grow a lot faster and steal away even more resources from the virus. Plus, they don’t encode any virus proteins, which renders them powerless inside a cell, says Yin.

Although the diversionary molecules do need resources from the cell to work, Yin clarifies, “they essentially shut down virus growth while expending only a small fraction of the resources that the virus would normally use.”

Yin and Kim analyzed the potency of this parasitic antiviral approach in computational models where E. coli had been infected with a particular virus. For the diversionary molecule, they introduced a short piece of RNA that competes for the same resources as the infectious virus to replicate. The researchers note that the models are based on experimental data and decades of biophysical and biochemical studies.

The analysis shows that when the parasitic molecule was absent, the virus had produced more than 10,000 copies of itself in less than 20 minutes after infection. In the presence of the parasitic molecule, however, no new progeny of the virus existed. The analysis, says Yin, also shows that the diversionary molecules had grown in number by more than 10,000-fold just 10 minutes after infection, further suggesting that the molecule successfully stole away resources from the virus.

“The parasitic strategy outperformed the non-parasitic strategies at all levels,” says Kim. “It inhibited viral growth, even at a low dose, placed minimal demands on the intracellular resources of the host cell and was effective when introduced either before or during the infection cycle.” One other important finding, he adds, is that the strategy created no obvious way for the virus to develop drug-resistant strains.

“Our calculations suggest that this antiviral strategy is a very effective approach and one that is very difficult for a virus to overcome,” says Yin. “There are definite technical challenges to implementing this approach, but the findings do open the door to a broader way of thinking about antiviral strategies.”

Yin says the next step is for researchers to test these ideas inside living cells.

Emily Carlson (608) 262-9772, emilycarlson@wisc.edu